Kv7 channel activators compositions and methods of use

ABSTRACT

Provided herein are optionally substituted benzoimidazol-1,2-yl amides, pharmaceutical compositions comprising a therapeutically effective amount of such compounds and a pharmaceutically acceptable excipient, and methods of treating Kv7 associated diseases, such as, epilepsy, amyotrophic lateral sclerosis, various types of pain, hyperexcitability, a dyskinesia, dystonia, mania and tinnitus with such compounds and pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/644,902 filed Mar. 19, 2018 and U.S. Provisional Application No.62/644,932 filed Mar. 19, 2018 and U.S. Provisional Application No.62/663,438 filed Apr. 27, 2018 and U.S. Provisional Application No.62/697,198 filed Jul. 12, 2018. The disclosures of each of theseapplications are incorporated herein by reference.

GOVERNMENT INTERESTS

This invention was made with United States Government support underGrant No. U44NS093160 awarded by the National Institute of NeurologicalDisorders and Stroke of the National Institutes of Health. The UnitedStates Government has certain rights in the invention.

SUMMARY

Potassium (K⁺) channels, present on the plasma membranes of most celltypes, are the most diverse class of all ion channels and are associatedwith a wide range of physiological functions including the regulation ofthe electrical properties of excitable cells. The primary pore-forming(a) subunits of these highly selective cation channels are divided intothree primary structural classes based on the number of transmembrane(TM)-spanning regions and pore (P) regions: currently there are known tobe 6TM/1P, 2TM/1P and 4TM/2P K⁺ channels. The Kv7 genes (originallytermed KCNQ, a name assigned by the HUGO Gene Nomenclature Committee(HGNC)) were assigned to a subfamily of voltage-gated K⁺ channels by theInternational Union of Pharmacology (IUPHAR). The Kv7 subfamily consistsof five homologous pore-forming α subunits, Kv7.1-7.5, that have astructure typical of voltage-gated K⁺ channels with 6TM-spanning regions(S1-S6) flanked by intracellular N-terminal and C-terminal domains, atypical voltage-sensor domain located in S4 comprised of alternatingpositively-charged residues and a single P region between S5 and S6 ofeach subunit. The channels are formed as tetramers of the primary αsubunits, either as homotetramers or heterotetramers. Neurons are knownto express Kv7 channels comprised of Kv7.2-7.5 α subunits. Some of thesegene products may be exclusively neuronal while others, such as Kv7.4and Kv7.5, can be found in other tissues such as smooth and skeletalmuscle.

Native M-channels, and the corresponding macroscopic M-current, werefirst characterized in amphibian sympathetic neurons. M-channels werenotable because they were slowly activating and non-inactivating, activeat membrane potentials at or near the resting membrane potential ofneurons and muscarinic cholinergic agonists produced a reduction in theM-current, demonstrating a direct and inhibitory link between G-proteincoupled receptors (GPCRs) and a physiological K⁺ current. It was notuntil the cloning of this subfamily of genes that the pharmacologicaland biophysical identity was established between Kv7.2/7.3 (and likelyKv7.5/7.3) heteromultimers and the elusive ‘M’-channel, providingsignificant new evidence for their importance in neuronal regulation.

The distributions of these channels, both regionally anddevelopmentally, as well as their biophysical characteristics, supporttheir role in providing enduring resistance to depolarizing excitatoryinfluences. Under physiological conditions, as was demonstrated withnative M-channels, they can be very effective at regulating thesub-threshold excitability of certain neuronal populations withsignificant roles in regulating the frequency and ultimately the patternof action potential discharge in many types of neurons. Their importancein neuronal regulation was punctuated by the discovery that neuronal Kv7mutations lead to benign familial neonatal convulsions (BFNC),indicating that reduction or removal of the influence of Kv7.2 and Kv7.3channels can dramatically alter neuronal excitability. Mutation analysesdemonstrated their involvement in BFNC and suggested their utility astargets for anti-epileptic drugs (AEDs).

Unlike established pharmacological terminology for GPCRs, the mode ofaction of K⁺ channel modulators, in particular compounds that activatethe channel, is still being refined. The application of voltage-clamptechniques to the study of ion channel pharmacology enabled detailedbiophysical studies on either whole-cell currents or single channels,allowing some characterization of the nature of compound-channelinteractions but not preventing ongoing confusion around theterminology. The term opener or activator is commonly used throughoutthe literature but does not adequately describe the mode of action ofall these ‘positive modulator’ compounds. In general, openers oractivators are expected to increase the open probability of the channelor increase macroscopic current amplitude, but this nomenclature isreally too simplistic. For example, retigabine, the first publiclydisclosed Kv7 opener, has a complex and interesting profile in that ithas inhibitory activity at higher membrane potentials. Neuronal Kv7channel openers may work in concert with the activity of a channel overthe ‘normal’ activation-voltage range and enhance currents withoutsignificantly affecting the activation threshold while others cansignificantly alter the activation threshold. In addition, some openersappear to remove the voltage-dependence of activation entirely. Whetherthese effects represent some continuum is currently unclear since theeffects are often concentration-dependent. Clearly, the modes ofinteraction of compounds that can increase channel current are complexand in most cases not well understood and the implications of theseprofiles on neuronal responsiveness and systems physiology are alsounclear. Retigabine is modestly potent, not highly specific, but it is avery effective opener of Kv7.2, Kv7.5 and heteromultimeric Kv7 channels.Its effects are characterized by a significant increase in channelcurrent over a narrow voltage range. As mentioned above, at morepositive voltages the opener is less effective and under some conditionschannel current significantly decreases at more positive voltagesrelative to control currents (this ‘crossover’ voltage-dependence ofopener action is a characteristic of many neuronal Kv7 channel openers).This effect is also concentration-dependent and is more pronounced athigher concentrations.

Provided herein are compounds that can be potent and/or at least biasedfor the Kv7.2/7.3 heteromultimer over the Kv7.4 homomultimer. Thesecompounds may have reduced untoward side effects as compared toretigabine.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that any invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.Moreover, the processes, compositions, and methodologies described inparticular embodiments are interchangeable. Therefore, for example, acomposition, dosage regimen, route of administration, and so ondescribed in a particular embodiment may be used in any of the methodsdescribed in other particular embodiments. It is also to be understoodthat the terminology used in the description is for the purpose ofdescribing the particular versions or embodiments only, and is notintended to limit the scope of the present invention, which will belimited only by the appended claims. Unless clearly defined otherwise,all technical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art. Although anymethods similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the present invention, thepreferred methods are now described. All publications and referencesmentioned herein are incorporated by reference. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

It must be noted that, as used herein, and in the appended claims, thesingular forms “a”, “an”, and “the” include plural reference unless thecontext clearly dictates otherwise.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%. Unless otherwise indicated, allnumbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth used in thespecification and claims are to be understood as being modified in allinstances by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

“Administering,” when used in conjunction with a therapeutic, means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a subject whereby the therapeutic positivelyimpacts the tissue to which it is targeted. “Administering” acomposition may be accomplished by oral administration, injection,infusion, absorption or by any method in combination with other knowntechniques. “Administering” may include the act of self-administrationor administration by another person such as a healthcare provider or adevice.

As used herein, the terms “comprising,” “comprise,” “comprises,” and“comprised” are inclusive or open-ended and do not exclude additional,unrecited elements or method steps.

As used herein, the term “consists of” or “consisting of” means that thecomposition or method includes only the elements, steps, or ingredientsspecifically recited in the particular embodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the composition or method includes only thespecified materials or steps and those that do not materially affect thebasic and novel characteristics of the claimed invention.

The term “improves” is used to convey that the present invention refersto the overall physical state of an individual to whom an active agenthas been administered. For example, the overall physical state of anindividual may “improve” if one or more symptoms of a condition, diseaseor disorder, such as a neurodegenerative disorder, are alleviated byadministration of an active agent. “Improves” may also refer to changesin the appearance, form, characteristics, and/or physical attributes oftissue, or any combination thereof, to which it is being provided,applied, or administered.

The term “inhibit,” “suppress,” “decrease,” “interfere,” and/or “reduce”(and like terms) generally refers to the act of reducing, eitherdirectly or indirectly, a function, activity, or behavior relative tothe natural, expected, or average or relative to current conditions.

As used herein, the phrase “Kv7 associated diseases” is a disease,disorder, or condition: associated with a mutation in the KCNQ2 gene;associated with a mutation in the KCNQ3 gene; associated with a mutationin the KCNQ4 gene; associated with a mutation in the KCNQ5 gene;associated with genes encoding Kv7 potassium channels; associated with anon-mutated Kv7 potassium channel, but dysfunctional Kv7 potassiumchannel; associated with the hyperexcitability of cells that arebelieved to cause the disease, disorder or condition; or a combinationthereof. Regardless of causation, these Kv7 associated diseases,disorders or conditions can be treated by the activation of the Kv7potassium channel, even though the Kv7 potassium channel may not be adirect or indirect cause of the disease, disorder or condition.

Examples of a Kv7 associated disorder in relation to a mutation in theKCNQ2 gene include but are not limited to benign familial neonatalseizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatalepileptic encephalopathy). Examples of a Kv7 associated disorder inrelation to a mutation in the KCNQ3 gene include but are not limited toBFNS or KCNQ3-related developmental disability. Examples of a Kv7associated disorder in relation to a mutation in the KCNQ4 gene includebut are not limited to autosomal dominant nonsyndromic hearing loss.Examples of a Kv7 associated disorder in relation to a mutation in theKCNQ5 gene include but are not limited to nonsyndromic intellectualdisability or epileptic encephalopathy. Examples of a disorderassociated with the hyperexcitability of cells that are believed tocause the disease, disorder or condition include but are not limited tofocal clonic seizures, generalized tonic-clonic seizures, neuropathicpain, overactive bladder; or smooth muscle disorders, or a combinationthereof.

In each of the embodiments disclosed herein, the compositions andmethods may be utilized with or on a subject in need of such treatment,which may also be referred to as “in need thereof” As used herein, thephrase “in need thereof” means that the subject has been identified ashaving a need for the particular method or treatment and that thetreatment has been given to the subject for that particular purpose.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, or prevent, or any combination thereof, an unwantedcondition, disorder or disease of a subject.

As used herein, the term “patient” and “subject” are interchangeable andmay be taken to mean any living organism, which may be treated withcompounds of the present invention. As such, the terms “patient” and“subject” may include, but are not limited to, any non-human mammal,primate or human. In some embodiments, the “patient” or “subject” is anadult, child, infant, or fetus. In some embodiments, the “patient” or“subject” is a human. In some embodiments, the “patient” or “subject” isa mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, primates, or humans.

The terms “therapeutically effective amount” or “therapeutic dose” asused herein are interchangeable and may refer to the amount of an activeagent or pharmaceutical compound or composition that elicits a clinical,biological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinical professional. A clinical, biological or medicalresponse may include, for example, one or more of the following: (1)preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display pathology or symptoms of the disease, condition ordisorder, (2) inhibiting a disease, condition or disorder in anindividual that is experiencing or displaying the pathology or symptomsof the disease, condition or disorder or arresting further developmentof the pathology and/or symptoms of the disease, condition or disorder,and (3) ameliorating a disease, condition or disorder in an individualthat is experiencing or exhibiting the pathology or symptoms of thedisease, condition or disorder or reversing the pathology and/orsymptoms experience or exhibited by the individual.

The term “treat,” “treated,” or “treating” may be taken to meanprophylaxis of a specific disorder, disease or condition, alleviation ofthe symptoms associated with a specific disorder, disease or conditionand/or prevention of the symptoms associated with a specific disorder,disease or condition. In some embodiments, the term refers to slowingthe progression of the disorder, disease or condition or alleviating thesymptoms associated with the specific disorder, disease or condition. Insome embodiments, the term refers to alleviating the symptoms associatedwith the specific disorder, disease or condition. In some embodiments,the term refers to alleviating the symptoms associated with the specificdisorder, disease or condition. In some embodiments, the term refers torestoring function which was impaired or lost due to a specificdisorder, disorder or condition.

“Pharmaceutically acceptable salt” is meant to indicate those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of a patient without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al. (1977) J. Pharm.Sciences, Vol. 6, 1-19, describes pharmaceutically acceptable salts indetail. A pharmaceutically acceptable “salt” is any acid addition salt,preferably a pharmaceutically acceptable acid addition salt, including,but not limited to, halogenic acid salts such as hydrobromic,hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acidsalt such as, for example, nitric, perchloric, sulfuric and phosphoricacid salt; an organic acid salt such as, for example, sulfonic acidsalts (methanesulfonic, trifluoromethanesulfonic, ethanesulfonic,benzenesulfonic or p-toluenesulfonic, acetic, malic, fumaric, succinic,citric, benzonic, gluconic, lactic, mandelic, mucic, pamoic,pantothenic, oxalic and maleic acid salts; and an amino acid salt suchas aspartic or glutamic acid salt. The acid addition salt may be a mono-or di-acid addition salt, such as a di-hydrohalogic, di-sulfuric,di-phosphoric or di-organic acid salt. In all cases, the acid additionsalt is used as an achiral reagent which is not selected on the basis ofany expected or known preference for the interaction with orprecipitation of a specific optical isomer of the products of thisdisclosure.

Unless otherwise indicated, when a compound or chemical structuralfeature such as aryl is referred to as being “optionally substituted,”it includes a feature that has no substituents (i.e. unsubstituted), ora feature that is “substituted,” meaning that the feature has one ormore substituents. The term “substituent” has the broadest meaning knownto one of ordinary skill in the art, and includes a moiety that replacesone or more hydrogen atoms attached to a parent compound or structuralfeature. In some embodiments, a substituent may be an ordinary organicmoiety known in the art, which may have a molecular weight (e.g. the sumof the atomic masses of the atoms of the substituent) of 15 g/mol to 50g/mol, 15 g/mol to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol to 200g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In someembodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10,or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, whereineach heteroatom may independently be: N, O, S, Si, F, Cl, Br, or I;provided that the substituent includes one C, N, O, S, Si, F, Cl, Br, orI atom. Examples of substituents include, but are not limited to, alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate,thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl,sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc.

For convenience, the term “molecular weight” is used with respect to amoiety or part of a molecule to indicate the sum of the atomic masses ofthe atoms in the moiety or part of a molecule, even though it may not bea complete molecule.

The structures associated with some of the chemical names referred toherein are depicted below. These structures may be unsubstituted, asshown below, or a substituent may independently be in any positionnormally occupied by a hydrogen atom when the structure isunsubstituted. Unless a point of attachment is indicated by

attachment may occur at any position normally occupied by a hydrogenatom.

As used herein, the term “alkyl” has the broadest meaning generallyunderstood in the art, and may include a moiety composed of carbon andhydrogen containing no double or triple bonds. Alkyl may be linearalkyl, branched alkyl, cycloalkyl, or a combination thereof, and in someembodiments, may contain from one to thirty-five carbon atoms. In someembodiments, alkyl may include C₁₋₁₀ linear alkyl, such as methyl(—CH₃), methylene (—CH₂—), ethyl (—CH₂CH₃), ethylene (—C₂H₄—), n-propyl(—CH₂CH₂CH₃), propylene (—C₃H₆—), n-butyl (—CH₂CH₂CH₂CH₃), n-pentyl(—CH₂CH₂CH₂CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), etc.; C₃₋₁₀ branchedalkyl, such as C₃H₇ (e.g. iso-propyl), C₄H₉ (e.g. branched butylisomers), C₅H₁₁ (e.g. branched pentyl isomers), C₆H₁₃ (e.g. branchedhexyl isomers), C₇H₁₅ (e.g. branched heptyl isomers), etc.; C₃₋₁₀cycloalkyl, such as C₃H₅ (e.g. cyclopropyl), C₄H₇ (e.g. cyclobutylisomers such as cyclobutyl, methylcyclopropyl, etc.), C₅H₉ (e.g.cyclopentyl isomers such as cyclopentyl, methylcyclobutyl,dimethylcyclopropyl, etc.), C₆H₁₁ (e.g. cyclohexyl isomers), C₇H₁₃ (e.g.cycloheptyl isomers), bicyclo[1.1.1]pentane, norbornane, etc.; and thelike.

With respect to an optionally substituted moiety such as optionallysubstituted alkyl, a phrase such as “optionally substituted C₁₋₁₂ alkyl”refers to a C₁₋₁₂ alkyl that may be unsubstituted, or may have 1 or moresubstituents, and does not limit the number of carbon atoms in anysubstituent. Thus, for example, CH₂(CH₂)₁₁OCH₃ is optionally substitutedC₁₋₁₂ alkyl because the parent alkyl group has 12 carbon atoms. A phrasesuch as “C₁₋₁₂ optionally substituted alkyl” refers to unsubstitutedC₁₋₁₂ alkyl, or substituted alkyl wherein the alkyl parent and allsubstituents together have from 1-12 carbon atoms. For example,CH₂CH₂OCH₃ is C₁₋₁₂ optionally substituted alkyl because the alkyl group(e.g. ethyl) and the substituent (e.g. methoxy) together contain 3carbon atoms. Similar conventions may be applied to other optionallysubstituted moieties such as aryl and heterocyclyl.

Substituents on alkyl may be the same as those described generallyabove. In some embodiments, substituents on alkyl are independentlyselected from F, Cl, Br, I, CN, CO₂H, —O-alkyl, ester groups, acyl,amine groups, amide groups, phenyl (including fused phenyl resultingoptionally substituted alkyl such as indenyl, where the phenylsubstituent is fused to the parent alkyl moiety), and may have amolecular weight of about 15 to about 100 or about 500.

As used herein, the term “aryl” has the broadest meaning generallyunderstood in the art, and may include an aromatic ring or aromatic ringsystem such as phenyl, naphthyl, etc.

The term “heterocyclyl” includes any ring or ring system containing aheteroatom such as N, O, S, P, etc. Heterocyclyl includes heteroarylrings or ring systems (such as those listed below) and non-aromaticrings or ring systems. Examples of non-aromatic heterocyclyl includeazetidinyl, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl,thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl,tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, etc.

The term “heteroaryl” also has the meaning understood by a person ofordinary skill in the art, and includes an “aryl” which has one or moreheteroatoms in the ring or ring system, such as pyridinyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl,isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl,benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.

As used herein, the term “carbocyclyl” has the broadest meaninggenerally understood in the art and includes rings free of heteroatoms,such as cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.; cycloalkenyl, e.g. cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl; cycloalkynyl, e.g. cyclopropynyl,cyclobutynyl, cyclopentynyl, cyclohexynyl; bridged cycloalkyl, e.g.bicyclo[1.1.1]pentane, norbornane, etc.; as well as aryl rings free ofheteroatoms.

If stereochemistry is not indicated, a name or structural representationincludes any stereoisomer or any mixture of stereoisomers and Applicantreserves the right to specifically identify and claim a compound as asingle stereoisomer or any particular mixture of stereoisomers.

Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds according to embodimentsherein possess two or more asymmetric centers, they may additionallyexist as diastereomers. Embodiments herein include all such possiblestereoisomers as substantially pure resolved enantiomers, racemicmixtures thereof, as well as mixtures of diastereomers. In someembodiments, the formulas are shown without a definitive stereochemistryat certain positions. Embodiments herein include all stereoisomers ofsuch formulas and pharmaceutically acceptable salts thereof.Diastereoisomeric pairs of enantiomers may be separated by, for example,fractional crystallization from a suitable solvent, and the pair ofenantiomers thus obtained may be separated into individual stereoisomersby conventional means, for example by the use of an optically activeacid or base as a resolving agent or on a chiral HPLC column. Further,any enantiomer or diastereomer of a compound of the general formula maybe obtained by stereospecific or stereoselective synthesis usingoptically pure or enantioenriched starting materials or reagents ofknown configuration. The scope of embodiments herein as described andclaimed encompasses the racemic forms of the compounds as well as theindividual enantiomers, diastereomers, and stereoisomer-enrichedmixtures and Applicant reserves the right to specifically identify andclaim a compound in any such form.

The compounds disclosed herein can exist as and therefore include allstereoisomers, conformational isomers and mixtures thereof in allproportions as well as isotopic forms such as deuterated compounds andApplicant reserves the right to specifically identify and claim acompound in any such form.

Disclosed herein are examples of developments in Kv7.2/7.3 structureactivity relationships that have resulted in significant gains inpotency against this ion channel target. The known Kv7 activatorezogabine has an EC₅₀ of 1.1 μM as characterized in the Kv7.2/7.3 FluxORPotassium Ion Channel Assay (Invitrogen, F20015). Species described in,US 2017/0114022, US 2018/0148419, and WO 2018/081825 that were tested inthe thallium flux assay possess a range of Kv7.2/7.3 potenciesdemonstrated by their EC₅₀ values, the majority of which lie in theactivity range between 1 and 10 μM and only a few (11%) with EC₅₀ values≤0.30 μM. The genera and species described herein distinguish themselvesas Kv7 activators from the previous chemical matter as demonstrated bytheir superior activities on Kv7.2/7.3; the thallium flux EC₅₀ values ofthese compounds range from ≤1 μM to ≤0.3 μM, including a number of thesenew examples that possess EC₅₀ values ≤0.05 μM. In certain preferredembodiments, compounds of the present application possess a smallnon-hydrogen substituent at the R² position, in combination withincreased substitution at the position beta to the carbonyl of

the optionally substituted, hydrophobic alkyl group at the Y position,as in any of structural formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, often result in a Kv7.2/7.3 EC₅₀<1 μM.

Some embodiments include a compound represented by Formula 1C:

With respect to Formula 1C, Bz can be optionally substitutedbenzoimidazol-1,2-yl. If the benzoimidazol-1,2-yl is substituted, it mayhave 1, 2, 3, or 4 substituents. Any substituent may be included on thebenzoimidazol-1,2-yl. In some embodiments, some or all of thesubstituents on the benzoimidazol-1,2-yl may have: from 0 to 10 carbonatoms and from 0 to 10 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I (provided that there is at least1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500g/mol. In some embodiments, some or all of the substituents may eachhave a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to50 Da, and consist of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br. In someembodiments, Bz can be optionally substituted benzoimidazol-1,2-diyl. Insome embodiments, Bz can be optionally substitutedbenzoimidazol-1,2,6-triyl.

For example, with respect to Formula 1C, the substituents of Bz may beC₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclicC₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc.,which may be optionally substituted; C₁₋₁₀ optionally substituted alkoxysuch as OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁,cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I;OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as—O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; aC₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or aC₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of Bz may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

Some embodiments of Formula 1C may include a compound represented byFormula 2C:

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, D is optionally substituted C₃₋₆carbocyclyl or C₂₋₅ heterocyclyl. If D is substituted cyclobutyl, it mayhave 1, 2, 3, 4, 5, 6, or 7 substituents. If D is substituted phenyl, itmay have 1, 2, 3, 4, or 5 substituents. If D is substituted isoxazolyl,it may have 1 or 2. Substituents. D may include any substituent. In someembodiments, some or all of the substituents of D may have: from 0 to 10carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I (provided that there is at least1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500g/mol. In some embodiments, some or all of the substituents may eachhave a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to50 Da, and consist of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, the substituents of D may be C₁₋₁₀optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅,C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁,bicyclo[1.1.1]pentane, norbornane, etc., which may be optionallysubstituted; C₁₋₁₀ optionally substituted alkoxy such as OCH₃, OC₂H₅,OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclic OC₅H₉, OC₆H₁₃,cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy, such asOCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as —O₂CCH₃, —CO₂CH₃,—O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone suchas —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such asNH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In some embodiments, asubstituent of D may be F, Cl, Br, I, CN, NO₂, C₁₋₄ alkyl, C₁₋₄alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄ CO₂-alkyl,NH₂, or C₁₋₄ alkylamino.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is:

or optionally substituted C₂₋₄ alkyl.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is optionallysubstituted cyclobutyl, optionally substituted phenyl, optionallysubstituted isoxazolyl, bicyclo[1.1.1]pentane, norbornane, or isopropyl.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is optionallysubstituted cyclobutyl. In some embodiments, D is cyclobutyl. In someembodiments, D is

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is isopropyl.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is t-butyl, ortert-butyl.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D isbicyclo[1.1.1]pentane.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is optionallysubstituted phenyl. In some embodiments D is

or

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is optionallysubstituted pyridinyl, such as optionally substituted pyridin-2-yl,pyridin-3-yl, or pyridin-4-yl. In some embodiments, D is

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments, D is optionallysubstituted isoxazolyl. In some embodiments, D is

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, A is C₁₋₅ alkyl, such as linear orbranched

linear or branched

linear or branched

linear or branched

linear or branched

linear or branched

containing one ring,

containing one ring,

containing one ring,

containing one ring, or

containing a bicyclic ring system.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, X is H, F, CH₃, SCF₃, CF₃, optionallysubstituted C₂₋₁₀ alkyl, optionally substituted phenyl, or optionallysubstituted pyridinyl. In some embodiments, X is H. In some embodiments,X is CH₃. In some embodiments, X is F. In some embodiments, X is CF₃.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, if X is substituted phenyl, it may have1, 2, 3, 4, or 5, substituents. If X is substituted pyridinyl, it mayhave 1, 2, 3, or 4 substituents. In some embodiments, some or all of thesubstituents of X may have: from 0 to 10 carbon atoms and from 0 to 10heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl,Br, or I (provided that there is at least 1 non-hydrogen atom); and/or amolecular weight of 15 g/mol to 500 g/mol. In some embodiments, some orall of the substituents may each have a molecular weight of 15 Da to 200Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,F, Cl, or Br.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, the substituents of X may be C₁₋₁₀optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅,C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., whichmay be optionally substituted; C₁₋₁₀ optionally substituted alkoxy suchas OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, cyclic OC₅H₁₁,cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I;OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as—O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; aC₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or aC₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of X may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, SCF₃, or C₁₋₄ alkylamino.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, Y is H, F, Cl, Br, I, or a moietyhaving a molecular weight of 15 Da to 300 Da and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br. In some embodiments, Y is H, F, Cl, Br, I, CN,—COH, C₁₋₆—CO-alkyl, CF₃, OH, C₁₋₅ O-alkyl, C₃₋₆ amino, or C₃₋₆fluoroamino. In some embodiments, Y is H, F, CF₃, OH, C₁₋₅ O-alkyl, C₃₋₆amino, or C₃₋₆ fluoroamino. In some embodiments, Y is H. In someembodiments, Y is OH. In some embodiments, Y is F. In some embodiments,Y is CF₃. In some embodiments, Y is C₁₋₃ O-alkyl, such as —OCH₃, OC₂H₅,OC₃H₇, etc. In some embodiments, Y is C₃₋₆ fluoroamino. In someembodiments, Y is optionally substituted tetrahydropyranyl, such as

In some embodiments Y may include a C₁₋₅ alkyl that may include one ortwo C₃₋₆ carbocyclyl rings. In some embodiments, wherein Y includes atleast one carbocyclyl rings, the rings may be connected to each other.In some embodiments, Y is —C(CF₃)₂OH (or1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments Y is

(or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y isdimethylamino.

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is C₂₋₈ alkyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is C₂₋₈ hydroxyalkyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is C₂₋₈ fluoroalkyl such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is C₂₋₈ alkoxyalkyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is C₂₋₈ hydroxyfluoroalkyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is optionally substituted 2-hydroxy-2-phenylethyl, such as

In some embodiments

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is optionally substituted 2-hydroxy-2-phenylpyridinyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies, in some embodiments

is optionally substituted C₂₋₈ fluoroaminoalkyl, such as

To any relevant embodiment or structural representation of Formula 1C or2C herein the following applies. Generally R¹⁻¹⁸ may be H or anysubstituent, such as a substituent having 0 to 12 atoms or 0 to 6 carbonatoms and 0 to 5 heteroatoms, wherein each heteroatom is independently:O, N, S, F, Cl, Br, or I, and/or having a molecular weight of 15 g/molto 300 g/mol. Any of R¹⁻¹⁸ may comprise: a) 1 or more alkyl moietiesoptionally substituted with, or optionally connected by or to, b) 1 ormore functional groups, such as C═C, C≡C, CO, CO₂, CON, NCO₂, OH, SH, O,S, N, N═C, F, Cl, Br, I, CN, NO₂, CO₂H, NH₂, etc.; or may be asubstituent having no alkyl portion, such as F, Cl, Br, I, NO₂, CN, NH₂,OH, COH, CO₂H, etc. In some embodiments, each of R¹⁻¹⁸ is independentlyH, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to300 Da, 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 60 Da, andconsisting of 2 to 5 chemical elements, wherein the chemical elementsare independently C, H, O, N, S, F, Cl, or Br.

With respect to any relevant structural representation of Formula 1C or2C, some non-limiting examples of R¹⁻¹⁸ may include R^(A), F, Cl, Br,CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B),COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁻¹⁸ may be H; F; Cl; Br; CN; C₁₋₃ fluoroalkyl, such asCHF₂, CF₃, etc; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propylisomers (e.g. n-propyl and isopropyl), cyclopropyl, butyl isomers,cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), pentylisomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.;optionally substituted C₁₋₇ alkoxy, such as —O-methyl, —O-ethyl, isomersof —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, —O-benzyl, etc.; C₁₋₄hydroxyalkyl, such as —CH₂OH, —C₂H₄—OH, —C₃H₆—OH, C₄H₈—OH, etc.;C₂₋₅—CO₂-alkyl, such as —CO₂—CH₃, —CO₂—C₂H₅, —CO₂—C₃H₇, —CO₂—C₄H₉, etc.

With respect to any relevant structural representation of Formula 1C or2C, each R^(A) may independently be H, or C₁₋₁₂ alkyl, including: linearor branched alkyl having a formula C_(a)H_(2a+1), or cycloalkyl having aformula C_(a)H_(2a−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12, such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇,C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl ofa formula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(A) may be H or optionally substituted C₁₋₆ alkyl.In some embodiments, R^(A) may be H or optionally substituted C₁₋₃alkyl. In some embodiments, R^(A) may be H or CH₃. In some embodiments,R^(A) may be H.

With respect to any relevant structural representation of Formula 1C or2C, each R^(B) may independently be H, or C₁₋₁₂ alkyl, including: linearor branched alkyl having a formula C_(a)H_(2a+1), or cycloalkyl having aformula C_(a)H_(2a−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12, such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇,C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl ofa formula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(B) may be H or C₁₋₃ alkyl. In some embodiments,R^(B) may be H or CH₃. In some embodiments, R^(B) may be H.

With respect to any relevant structural representation of Formula 1C or2C, such as Formula 2C, in some embodiments R¹ is H, F, Cl, Br, CN,OCH₃, OH, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl.In some embodiments, R¹ is H, Cl, Br, CN, OCH₃, OCHF₂, CHF₂, CF₃,—CO₂CH₂CH₃, —CH₂OH,

In some embodiments, R¹ is H. In some embodiments, R¹ is F. In someembodiments, R¹ is Cl. In some embodiments, R¹ is Br. In someembodiments, R¹ is CN. In some embodiments, R¹ is OCH₃. In someembodiments, R¹ is CHF₂. In some embodiments, R¹ is CF₃. In someembodiments, R¹ is —CO₂CH₂CH₃. In some embodiments, R¹ is —CH₂OH. Insome embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is —OCH₃, —OH, —OCHF₂, —O-benzyl, —CN, —CF₃,—CH₂OH, —COOCH₂CH₃, —C(CH₃)₂OH, —CHOHCH₂CH₃, —CHOHCH₃, —CHF₂, —CH(CH₃)₂,—C(CH₂CH₃)₂OH, —CH₂COOC H₂CH₃, —CH₂C(CH₃)₂OH, —CH₂COOH, or—CH₂CON(CH₃)₂. With respect to the embodiments recited in thisparagraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₅ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R² is H, F, Cl, Br, CN, OCH₃, OCF₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R² is H. In some embodiments, R² is F. In some embodiments, R² is CH₂OH.In some embodiments, R² is —CO₂CH₃. With respect to the embodimentsrecited in this paragraph, in some embodiments, the remaining groups ofR¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, theremaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH,NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R² is —CH₂OH, —CO₂Me, or —C(CH₃)₂OH.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R³ is H, F, Cl, Br, CN, OCH₃, OCHF₂, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R³ is H. In some embodiments, R³ is F. With respect to the embodimentsrecited in this paragraph, in some embodiments, the remaining groups ofR¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, theremaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH,NH₂, C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, orC₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁴ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁴ is H. In some embodiments, R⁴ is F. In some embodiments, R⁴ is CH₃.In some embodiments, R⁴ is CF₃. With respect to the embodiments recitedin this paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl,C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁵ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁵ is H. In some embodiments, R⁵ is CH₃. With respect to the embodimentsrecited in this paragraph, in some embodiments, the remaining groups ofR¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, theremaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH,NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁶ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁶ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁷ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁷ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁸ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁸ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R⁹ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R⁹ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R¹⁰ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R¹⁰ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R¹¹ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R¹¹ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R¹² is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R¹² is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R¹³ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R¹³ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula 1C or2C, in some embodiments R¹⁴ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₅ hydroxyalkyl. In some embodiments,R¹⁴ is H. In some embodiments, R¹⁴ is F. With respect to the embodimentsrecited in this paragraph, in some embodiments, the remaining groups ofR¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃fluoroalkyl, C₁₋₅ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, theremaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH,NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

In some embodiments of the invention, one or more hydrogen atoms isreplaced by a deuterium. It is well established that deuteration ofphysiologically active compounds offer the advantage of retaining thepharmacological profile of their hydrogen counterparts while positivelyimpacting their metabolic outcome. Selective replacement of one or morehydrogen with deuterium, in a compound of the present invention, couldimprove the safety, tolerability and efficacy of the compound whencompared to its all hydrogen counterpart.

Methods for incorporation of deuterium into compounds are wellestablished. Using metabolic studies established in the art, thecompound of the present invention can be tested to identify sites forselective placement of a deuterium isotope, wherein the isotope will notbe metabolized. Moreover these studies identify sites of metabolism asthe location where a deuterium atom would be placed.

In certain embodiments, the embodiments expressed herein do notencompass any compound expressly disclosed in U.S. Pat. No. 9,481,653,WO 2016/040952, U.S. Provisional No. 62/579,770, U.S. Provisional No.62/663,427, or U.S. Provisional No. 62/644,932.

In certain embodiments, the compounds of Formula 1C have a Kv7.2/7.3Thallium flux EC₅₀ of ≤10 μM. In certain embodiments, the compounds ofFormula 1C have a Kv7.2/7.3 Thallium flux EC₅₀ of ≤1 μM. In certainembodiments, the compounds of Formula 1C have a Kv7.2/7.3 Thallium fluxEC₅₀ of ≤0.3 μM.

Some embodiments of Formula 1C may include a compound represented byFormula 8a:

-   -   wherein        -   D is optionally substituted cyclobutyl or t-butyl;        -   A is C₁ alkyl;        -   X is substituted cyclobutyl, wherein the substituent is F;        -   Y is H;        -   R¹ is C₃ hydroxyalkyl or CN;        -   R² and R⁴ are H;        -   R³ is H or F; and        -   wherein when X is substituted with 2 fluorine atoms, the            fluorine atoms are not geminal;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 8b:

-   -   wherein        -   D is optionally substituted cyclobutyl or t-butyl, wherein            the optional substituents are selected from —CH₃ and F;        -   A is C₁ alkyl;        -   X is substituted cyclobutyl, wherein the substituent is F;        -   Y is H;        -   R¹ is selected from C₃ hydroxyalkyl, CN, or F;        -   R² is selected from H, F, or —OCF₃;        -   R³ is selected from H, F, or —OCH₃;        -   R⁴ is H or F; and        -   wherein when X is substituted with 2 fluorine atoms, the            fluorine atoms are not geminal;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 8c:

-   -   wherein        -   D is optionally substituted cyclobutyl, optionally            substituted phenyl, or t-butyl, wherein the optional            substituents are selected from —CH₃ and F;        -   A is C₁ alkyl;        -   X is substituted cyclobutyl, wherein the substituent is F;        -   Y is H;        -   R¹ is selected from H, C₃ hydroxyalkyl, CN, F, or Cl;        -   R² is selected from H, CN, F, Br, or —OCF₃;        -   R³ is selected from H, F, or —OCH₃;        -   R⁴ is H or F; and        -   wherein when X is substituted with 2 fluorine atoms, the            fluorine atoms are not geminal;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 9:

-   -   wherein        -   D is cyclobutyl;        -   A is C₁ alkyl;        -   X is optionally substituted cyclobutyl, wherein the optional            substituent is F;        -   Y is H;        -   R¹ is C₃ hydroxyalkyl;        -   R² and R⁴ are H;        -   R³ is F; and        -   wherein when X is substituted with 2 fluorine atoms, the            fluorine atoms are not geminal;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 10:

-   -   wherein        -   D is optionally substituted C₂₋₅ alkyl, wherein the optional            substituents are selected from —CH₃ and F;        -   A is C₁₋₆ alkyl;        -   X is H, F, —CH₃, —CF₃, —SCF₃, pyridinyl, optionally            substituted C₁₋₃ alkyl, optionally substituted phenyl, or            optionally substituted cyclobutyl, wherein the optional            substituent is F;        -   Y is H, F, —OH, or —CH₃;        -   R¹ is H, C₃₋₄ hydroxyalkyl, —CN, —OH, —CF₃, —OCHF₂,            optionally substituted C₃₋₅ heterocyclyl, optionally            substituted C₁₋₅ alkyl, optionally substituted C₁₋₇ alkoxy,            —NO^(A)R^(B), or halogen, wherein the optional substituents            are selected from —OH and F;        -   R² is H, halogen, —CN, —OCH₃, —COR^(A), —CF₃, —OCF₃,            optionally substituted C₁ alkyl, wherein the optional            substituents of R² are selected from —OCH₃ and —COR^(A);        -   R³ is H, halogen, —CF₃, —OCHF₂, —OCF₃, or —OCH₃;        -   R⁴ is H, halogen, or C₃ hydroxyalkyl; and        -   R^(A) and R^(B) are CH₃;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 11:

-   -   wherein        -   D is optionally substituted C₂₋₅ alkyl or optionally            substituted phenyl, wherein the optional substituents are            selected from —CH₃ and F;        -   A is C₁₋₆ alkyl;        -   X is H, F, —CH₃, —CF₃, —SCF₃, pyridinyl, optionally            substituted C₁₋₃ alkyl, optionally substituted phenyl, or            optionally substituted cyclobutyl, wherein the optional            substituent is F;        -   Y is H, F, —OH, or —CH₃;        -   R¹ is H, C₃₋₄ hydroxyalkyl, —CN, —OH, —CF₃, —OCHF₂,            optionally substituted C₃₋₅ heterocyclyl, optionally            substituted C₁₋₅ alkyl, optionally substituted C₁₋₇ alkoxy,            —NR^(A)R^(B), or halogen, wherein the optional substituents            are selected from —OH and F;        -   R² is H, halogen, —CN, —OCH₃, —COR^(A), —CF₃, —OCF₃,            optionally substituted C₁₋₂ alkyl, wherein the optional            substituents of R² are selected from —OCH₃ and —COR^(A);        -   R³ is H, halogen, —CF₃, —OCHF₂, —OCF₃, or —OCH₃;        -   R⁴ is H, halogen, or C₃ hydroxyalkyl; and        -   R^(A) and R^(B) are CH₃;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 12:

-   -   wherein        -   D is optionally substituted cyclobutyl, wherein the optional            substituent is —CH₃;        -   A is C₃ alkyl;        -   X is —CH₃;        -   Y is —CH₃;        -   R¹ is CN;        -   R² and R³ are F; and        -   R⁴ and is H;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 13:

-   -   wherein        -   D is t-butyl;        -   A is C₁ alkyl;        -   X is optionally substituted cyclobutyl, wherein the optional            substituent is F;        -   Y is H;        -   R¹ and R⁴ are F;        -   R² and R³ are H; and        -   wherein when X is substituted with 2 fluorine atoms, the            fluorine atoms are not geminal;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula 1C may include a compound represented byFormula 14:

-   -   wherein        -   D is optionally substituted C₂₋₅ alkyl, wherein the optional            substituents are selected from —CH₃;        -   A is C₁₋₆ alkyl;        -   X is H, F, —CH₃, —CF₃, optionally substituted C₁₋₃ alkyl,            optionally substituted phenyl, or optionally substituted            cyclobutyl, wherein the optional substituent is F;        -   Y is H, F, —OH, or —CH₃;        -   R¹ is H, C₃₋₄ hydroxyalkyl, —CN, —CF₃, —OCH₂CF₃, —OCHF₂,            optionally substituted C₃₋₅ heterocyclyl, optionally            substituted C₁₋₅ alkyl, optionally substituted C₁₋₇ alkoxy,            —NR^(A)R^(B), F, or Cl, wherein the optional substituents            are selected from —OH and F;        -   R² is F, Br, —CN, —OCH₃, —OCF₃, or —CF₃;        -   R³ is H, halogen, —CF₃, —OCHF₂, —OCF₃, or —OCH₃;        -   R⁴ is H, fluorine, or chlorine; and        -   R^(A) and R^(B) are CH₃;        -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula 11, when X is substituted with 2 fluorineatoms, the fluorine atoms are not geminal;

Some embodiments of Formula 11 are further illustrated by the compoundsof Group I, Group II, and Group III, or a pharmaceutically acceptablesalt thereof.

In some embodiments, provided herein are any one of the followingcompounds of Group I, or a pharmaceutically acceptable salt thereof:

In some embodiments, provided herein are any one of the followingcompounds of Group II, or a pharmaceutically acceptable salt thereof:

In some embodiments, provided herein are any one of the followingcompounds of Group III, or a pharmaceutically acceptable salt thereof:

Methods of Use

Embodiments of the present invention relate to a method of treating aKv7 associated disorder comprising administering a therapeuticallyeffective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11,12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1,or a pharmaceutically acceptable salt thereof, to a subject in needthereof. The disorder is selected from the group consisting of epilepsy,neonatal spasms, pain, migraine, a disorder of neurotransmitter release,a smooth muscle contractility disorder, a dyskinesia, dystonia, mania, ahearing disorder, neuropathic pain, inflammatory pain, persistent pain,cancer pain, postoperative pain, anxiety, substance abuse,schizophrenia, a bladder disorder, a vasculature disorder, tinnitus,benign familial neonatal seizures, epilepsy, neurological disease viareduced basal M-current (and subsequent neuronal hyperexcitability),sensorineural hearing impairment, intellectual disability, epilepticencephalopathy, treatment-resistant epilepsy, cortical atrophy,neurological impairment, infantile spasms with hypsarrhythmia,myoclonic-tonic seizures, myoclonic seizures, tonic seizures, absenceand focal-onset seizures with impaired awareness, congenitalneurological disorder with intellectual disability or epilepticencephalopathy, benign familial neonatal convulsions, severe epilepticencephalopathies, congenital neurodevelopmental disorder with phenotypesof nonsyndromic intellectual disability or epileptic encephalopathy,neonatal spasms, neonatal seizures, epileptic encephalopathy, benignfamilial neonatal convulsions type 1, benign familial neonatal seizures1, neonatal seizures associated with hypoxic-ischemic injury, epilepticspasms, epileptic encephalopathy, early infantile epilepticencephalopathy 7, early infantile epileptic encephalopathy with delayedpsychomotor development, generalized tonic seizures, abnormal globuspallidus morphology, apnea, cerebral edema, dystonia, facial erythema,muscular hypotonia, febrile seizures, hypoplasia of the corpus callosum,hypsarrhythmia, focal clonic seizure, generalized tonic-clonic seizures,myokymia, spastic tetraparesis, myokymia, gynecological systemdisorders, and combinations thereof. In embodiments, such compound maybe administered in a pharmaceutical composition as described herein.

In some embodiments, the gynecological system disorders are selectedfrom the group consisting of pre-term labor, post-partum hemorrhage,uterine atony, uterine perforation, uterine hyper-stimulation,menorrhagia, metrorrhagia, menometrorrhagia, dysmenorrhea andendometriosis.

KCNQ genes encode five Kv7 potassium channel subunits (1-5). Afunctional Kv7 potassium channel can be assembled using a combination ofthese five subunits arranged as homotetramers or heterotetramers. KCNQ2,KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and havebeen associated with a range of disorders involving neuronalexcitability.

Embodiments herein are directed to methods of treating a disorderassociated with a KCNQ subunit comprising administering atherapeutically effective amount of a compound of formula 1C, 2C, 8a,8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II,Group III, or Table 1, or a pharmaceutically acceptable salt thereof, toa subject in need thereof. Embodiments herein are directed to methods oftreating a disorder associated with a KCNQ2 subunit comprisingadministering a therapeutically effective amount of a compound offormula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound ofGroup I, Group II, Group III, or Table 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof. Embodimentsherein are directed to methods of treating a disorder associated with aKCNQ3 subunit comprising administering a therapeutically effectiveamount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, or a compound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to methods of treating a disorderassociated with a KCNQ4 subunit comprising administering atherapeutically effective amount of a compound of formula 1C, 2C, 8a,8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II,Group III, or Table 1, or a pharmaceutically acceptable salt thereof, toa subject in need thereof. Embodiments herein are directed to methods oftreating a disorder associated with a KCNQ5 subunit comprisingadministering a therapeutically effective amount of a compound offormula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound ofGroup I, Group II, Group III, or Table 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.

Embodiments herein are directed to methods of treating a disorderassociated with a mutation in a KCNQ subunit comprising administering atherapeutically effective amount of a compound of formula 1C, 2C, 8a,8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II,Group III, or Table 1, or a pharmaceutically acceptable salt thereof, toa subject in need thereof. Embodiments herein are directed to methods oftreating a disorder associated with a mutation in a KCNQ2 subunitcomprising administering a therapeutically effective amount of acompound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to methods of treating a disorderassociated with a mutation in a KCNQ3 subunit comprising administering atherapeutically effective amount of a compound of formula 1C, 2C, 8a,8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II,Group III, or Table 1, or a pharmaceutically acceptable salt thereof, toa subject in need thereof. Embodiments herein are directed to methods oftreating a disorder associated with a mutation in a KCNQ4 subunitcomprising administering a therapeutically effective amount of acompound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to methods of treating a disorderassociated with a mutation in a KCNQ5 subunit comprising administering atherapeutically effective amount of a compound of formula 1C, 2C, 8a,8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II,Group III, or Table 1, or a pharmaceutically acceptable salt thereof, toa subject in need thereof.

Compounds described herein have been shown to activate the Kv7 potassiumchannel. Mutations in the gene, KCNQ3, which encodes the Kv7 potassiumchannel result in a wide range of disorders. Embodiments herein aredirected to methods of treating a disorder associated with a KCNQ3mutation comprising administering a therapeutically effective amount ofa compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.The disorder associated with a KCNQ3 mutation is selected from the groupconsisting of benign familial neonatal seizures, epilepsy, neurologicaldisease via reduced basal M-current (and subsequent neuronalhyperexcitability), and any combination thereof.

Compounds described herein have been shown to activate the Kv7 potassiumchannel. Mutations in the gene, KCNQ4, which encodes the Kv7 potassiumchannel result in a wide range of disorders. Embodiments herein aredirected to methods of treating a disorder associated with a KCNQ4mutation comprising administering a therapeutically effective amount ofa compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.The disorder associated with a KCNQ4 mutation is sensorineural hearingimpairment.

Compounds described herein have been shown to activate the Kv7 potassiumchannel. Mutations in the gene, KCNQ5, which encodes the Kv7 potassiumchannel result in a wide range of disorders. Embodiments herein aredirected to methods of treating a disorder associated with a KCNQ5mutation comprising administering a therapeutically effective amount ofa compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.The disorder associated with a KCNQ5 mutation is selected from the groupconsisting of intellectual disability, epileptic encephalopathy,treatment-resistant epilepsy, cortical atrophy, neurological impairment,infantile spasms with hypsarrhythmia, myoclonic-tonic seizures,myoclonic seizures, tonic seizures, absence and focal-onset seizureswith impaired awareness, congenital neurological disorder withintellectual disability or epileptic encephalopathy, benign familialneonatal convulsions, severe epileptic encephalopathies, congenitalneurodevelopmental disorder with phenotypes of nonsyndromic intellectualdisability or epileptic encephalopathy, and any combination thereof.

Compounds described herein have been shown to activate the Kv7 potassiumchannel. Mutations in the gene, KCNQ2, which encodes the Kv7 potassiumchannel result in a wide range of disorders. Embodiments herein aredirected to methods of treating a disorder associated with a KCNQ2mutation comprising administering a therapeutically effective amount ofa compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, acompound of Group I, Group II, Group III, or Table 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.The disorder associated with a KCNQ2 mutation is selected from the groupconsisting of neonatal spasms, neonatal seizures, epilepsy, benignfamilial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy(KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benignfamilial neonatal seizures 1 (BFNS1), neonatal seizures associated withhypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy,early infantile epileptic encephalopathy 7 (EIEE7), early infantileepileptic encephalopathy with delayed psychomotor development,generalized tonic seizures, abnormal globus pallidus morphology, apnea,cerebral edema, dystonia, facial erythema, muscular hypotonia, febrileseizures, hypoplasia of the corpus callosum, hypsarrhythmia, focalclonic seizure, generalized tonic-clonic seizures, myokymia, spastictetraparesis, myokymia and combinations thereof. In embodiments, suchcompound may be administered in a pharmaceutical composition asdescribed herein.

Embodiments are directed to methods for treating conditions associatedwith hyperexcitability of cells in a subject comprising administering tothe subject a therapeutically effective amount of a compound of Group I,Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10,11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof,wherein the hyperexcitability is treated.

Embodiments are directed to methods for treating a Kv7 associateddisorder in a subject comprising administering to the subject atherapeutically effective amount of a compound of Group I, Group II,Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, or a pharmaceutically acceptable salt thereof, wherein thesymptoms of the disorder are alleviated or improved due to theactivation of Kv7 potassium channel.

Embodiments are directed to methods for treating neurodegenerativedisease in a subject comprising administering to the subject atherapeutically effective amount of a compound of Group I, Group II,Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, or a pharmaceutically acceptable salt thereof, wherein theneurodegenerative disease is treated. The compound of Group I, Group II,Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, may be administered to any individual exhibiting the symptoms ofa neurodegenerative disease or to individuals predisposed to aneurodegenerative disease. Non-limiting examples of neurodegenerativediseases that may be treated using a compound of Group I, Group II,Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, include amyotrophic lateral sclerosis (ALS), Huntington'sdisease, metabolically induced neurological damage, Alzheimer's disease,Pick's disease, senile dementia, age associated cognitive dysfunction,vascular dementia, multi-infarct dementia, Lewy body dementia,neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD,neurodegenerative movement disorder, ataxia, Friedreich's ataxia,multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis,seizure disorders, motor neuron disorder or disease, inflammatorydemyelinating disorder, Parkinson's disease, hepatic encephalopathy,chronic encephalopathy, chronic encephalitis, or any combinationthereof.

Embodiments are directed to methods for treating neurodegenerativedisease, such as amyotrophic lateral sclerosis, in a subject in needthereof comprising: administering to the subject a therapeuticallyeffective amount of a compound of Group I, Group II, Group III, or Table1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or apharmaceutically acceptable salt thereof, wherein the neurodegenerativedisease is treated. In embodiments, the subject is a subject withdefinite ALS, has amyotrophic lateral sclerosis symptom onset durationof less than about 18 months, plasma creatinine levels of about 72 M/Lor greater, concomitant riluzole administration, concomitantdexpramipexole administration, and combinations thereof.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject in need thereof comprising: administering to thesubject a therapeutically effective amount of a compound of Group I,Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10,11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof,wherein the amyotrophic lateral sclerosis is treated.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject diagnosed with definite amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of Group I, Group II, Group III, or Table1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or apharmaceutically acceptable salt thereof, wherein the amyotrophiclateral sclerosis is treated. In embodiments, the definite amyotrophiclateral sclerosis is as defined by the El Escorial diagnosis criteria.In embodiments, the subject is a subject with definite ALS, amyotrophiclateral sclerosis symptom onset duration of less than about 18 months,plasma creatinine levels of about 72 M/L or greater, concomitantriluzole administration, concomitant dexpramipexole administration, andcombinations thereof.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of Group I,Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10,11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof,wherein the subject is selected from a subject with definite amyotrophiclateral sclerosis, a subject with limb-onset amyotrophic lateralsclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, asubject with amyotrophic lateral sclerosis symptom onset duration ofless than about 18 months, a subject with a high level of serumcreatinine, a subject with low bicarbonate levels, a subject withconcomitant riluzole administration, a subject with concomitantdexpramipexole administration, and combinations thereof, and wherein theamyotrophic lateral sclerosis is treated. In certain embodiments, themethod further comprises monitoring said subject for any clinicalfeatures associated with amyotrophic lateral sclerosis. In certainembodiments, the method further comprises initiating therapy with atherapeutically effective amount of a compound of Group I, Group II,Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13,or 14, or a pharmaceutically acceptable salt thereof upon diagnosis ofamyotrophic lateral sclerosis. In certain embodiments, the subjectexhibits symptoms of amyotrophic lateral sclerosis. In certainembodiments, the subject has definite amyotrophic lateral sclerosis,probable amyotrophic lateral sclerosis, possible amyotrophic lateralsclerosis or suspected amyotrophic lateral sclerosis.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject diagnosed with definite amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of Group I, Group II, Group III, or Table1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or apharmaceutically acceptable salt thereof, wherein the amyotrophiclateral sclerosis is treated. In some embodiments definite amyotrophiclateral sclerosis is the presence of the El Escorial diagnosis criteria,amyotrophic lateral sclerosis symptom onset duration of less than about18 months, limb-onset amyotrophic lateral sclerosis, plasma creatininelevels of about 72 μM/L or greater, concomitant riluzole administration,concomitant dexpramipexole administration, an ALSFRS-R score of greaterthan 36.0, a pre-study progression rate greater than or equal to 0.8points per month, a percentage predicted relaxed (slow) vital capacity(SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domainscore of greater than 10.0 points, ALSFRS-R bulbar domain score orgreater than 9.0 points, an ALSFRS-R gross motor domain score of greaterthan 8.0 points, an abnormal neurological exam of the tongue, anabnormal neurological exam of the pharynx, larynx and swallowing, anabnormal neurological exam of the lower extremities, an abnormalneurological exam of the upper extremities, an abnormal neurologicalexam of the triceps, an abnormal neurological exam of the muscle massand bulk, an abnormal neurological exam of the bicep, an abnormalneurological exam, a pulse rate of greater than 81.0 beats per minute, adiastolic blood pressure of greater than 82.0 mmHg, a systolic bloodpressure of less than or equal to 117.0 mmHg, a creatinine value ofgreater than 72.0 μmol/L, a phosphorous value of less than or equal to1.090 μmol/L, a platelet count of less than or equal to 248.0×10⁹cells/L, a cholesterol value of less than or equal to 5.3 mmol/L, alactate dehydrogenase value of less than or equal to 161.0 U/L, acreatine phosphokinase value of less than or equal to 184.0 U/L, abicarbonate value of less than or equal to 21.6 mmol/L, a triglyceridelevel of less than or equal to 1.4 mmol/L, a uric acid level of greaterthan 320.0 μmol/L, a gamma-glutamyltransferase (GGT) level of greaterthan 37.0 U/L, a total bilirubin level of less than or equal to 6.0μmol/L, a urine pH of less than or equal to 5.5, or any combinationthereof.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject exhibiting symptoms of amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of Group I, Group II, Group III, or Table1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or apharmaceutically acceptable salt thereof, wherein the symptoms ofamyotrophic lateral sclerosis are treated. In some embodiments, thesubject exhibits clinical characteristics selected from definiteamyotrophic lateral sclerosis, amyotrophic lateral sclerosis symptomonset duration of less than about 18 months, limb-onset amyotrophiclateral sclerosis, plasma creatinine levels of about 72 μM/L or greater,concomitant riluzole administration, concomitant dexpramipexoleadministration, an ALSFRS-R score of greater than 36.0, a re-studyprogression rate greater than or equal to 0.8 points per month, apercentage predicted relaxed (slow) vital capacity (SVC) of less than orequal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0points, ALSFRS-R bulbar domain score or greater than 9.0 points, anALSFRS-R gross motor domain score of greater than 8.0 points, anabnormal neurological exam of the tongue, an abnormal neurological examof the pharynx, larynx and swallowing, an abnormal neurological exam ofthe lower extremities, an abnormal neurological exam of the upperextremities, an abnormal neurological exam of the triceps, an abnormalneurological exam of the muscle mass and bulk, an abnormal neurologicalexam of the bicep, an abnormal neurological exam, a pulse rate ofgreater than 81.0 beats per minute, a diastolic blood pressure ofgreater than 82.0 mmHg, a systolic blood pressure of less than or equalto 117.0 mmHg, a creatinine value of greater than 72.0 μmol/L, aphosphorous value of less than or equal to 1.090 μmol/L, a plateletcount of less than or equal to 248.0×109 cells/L, a cholesterol value ofless than or equal to 5.3 mmol/L, a lactate dehydrogenase value of lessthan or equal to 161.0 U/L, a creatine phosphokinase value of less thanor equal to 184.0 U/L, a bicarbonate value of less than or equal to 21.6mmol/L, a triglyceride level of less than or equal to 1.4 mmol/L, a uricacid level of greater than 320.0 μmol/L, a gamma-glutamyltransferase(GGT) level of greater than 37.0 U/L, a total bilirubin level of lessthan or equal to 6.0 μmol/L, a urine pH of less than or equal to 5.5, orany combination thereof.

In some embodiments, administering a therapeutically effective amount ofa compound of Group I, Group II, Group III, or Table 1 or Formulas 1C,2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceuticallyacceptable salt thereof, may include administering daily doses of about0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg toabout 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500mg, about 150 mg to about 1,500 mg, about 175 mg to about 1,500 mg,about 200 mg to about 1,500 mg, about 225 mg to about 1,500 mg, about250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mgto about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500mg, about 700 mg to about 1,500 mg, about 800 mg to about 1,500 mg,about 1,000 mg to about 1,500 mg, and about 1,200 mg to about 1,500 mg.

In some embodiments, the therapeutically effective amount of a compoundof Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b,8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable saltthereof, is selected from the group consisting of from about 0.1 mg toabout 1,000 mg, about 50 mg to about 1,000 mg per day, about 100 mg toabout 1,000 mg per day, about 150 mg to about 1,000 mg per day, about300 mg to about 1,000 mg per day, about 50 mg to about 300 mg per day,and about 150 mg to about 300 mg per day.

Such therapeutically effective amounts may be administered once a day orin equal, divided doses twice a day, three times a day, or four times aday. In some embodiments, administering a therapeutically effectiveamount comprises administering a dose equal to about half of a dailydose twice per day. In some embodiments, the dose is administered everyabout 12 hours. In some embodiments, administering a therapeuticallyeffective amount comprises administering about 25 mg two times per day,about 75 mg two times per day, about 150 mg two times per day, or about300 mg two times per day.

Pharmaceutical Compositions

Embodiments herein are directed to pharmaceutical compositionscomprising a therapeutically effective amount of a compound describedherein or acceptable salts thereof, such as a compound of Group I, GroupII, Group III, Table 1, or of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12,13, or 14, or pharmaceutically acceptable salts thereof. Pharmaceuticalformulations containing such compounds and a suitable carrier can be invarious forms including, but not limited to, solids, solutions, powders,fluid emulsions, fluid suspensions, semi-solids, and dry powdersincluding an effective amount of a compound of the invention. It is alsoknown in the art that the active ingredients can be contained in suchformulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, antioxidants, preservatives and the like. The means andmethods for administration are known in the art and an artisan can referto various pharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) both of which are herebyincorporated by reference in their entireties can be consulted.

In some embodiments, a single unit dose of a compound of Group I, GroupII, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12,13, or 14 or a pharmaceutically acceptable salt thereof, is selectedfrom the group consisting of about 0.1 mg to about 1,500 mg, about 1 mgto about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg,about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about175 mg to about 1,500 mg, about 200 mg to about 1,500 mg, about 225 mgto about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg,about 600 mg to about 1,500 mg, about 700 mg to about 1,500 mg, about800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg, and about1,200 mg to about 1,500 mg.

In some embodiments, a single unit dose amount of a compound of Group I,Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10,11, 12, 13, or 14 or a pharmaceutically acceptable salt thereof, isselected from group consisting of about 25 mg to about 5,000 mg, about50 mg to about 5,000 mg, about 100 mg to about 5,000 mg, about 150 mg toabout 5,000 mg, about 200 mg to about 5,000 mg, about 250 mg to about5,000 mg, about 300 mg to about 5,000 mg, about 400 mg to about 5,000mg, about 450 mg to about 5,000 mg, about 100 mg to about 3,000 mg,about 150 mg to about 3,000 mg, about 200 mg to about 3,000 mg, about250 mg to about 3,000 mg, about 300 mg to about 3,000 mg, about 400 mgto about 3,000 mg, 450 mg to about 3,000 mg, about 100 mg to about 1,000mg, about 150 mg to about 1,000 mg, about 200 mg to about 1,000 mg,about 250 mg to about 1,000 mg, about 300 mg to about 1,000 mg, about400 mg to about 1,000 mg, about 450 mg to about 1,000 mg, about 500 mgto about 1000 mg, and about 600 mg to about 1,000 mg. In someembodiments, the single unit dose amount may be 10 mg/day to 1,500mg/day, or about 100 mg/day to 600 mg/day. In some embodiments, suchsingle unit doses may be administered once per day or multiple times perday, such as twice per day or three times per day.

In some embodiments, the single unit dose further comprises apharmaceutically acceptable carrier.

The compounds can be formulated for parenteral or intravenousadministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection can be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Injectable preparations may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution.

Other embodiments include a compound prepared as described above whichare formulated as a solid dosage form for oral administration includingcapsules, tablets, pills, powders, and granules. In such embodiments,the active compound may be admixed with one or more inert diluent suchas sucrose, lactose, or starch. Such dosage forms may also comprise, asin normal practice, additional substances other than inert diluents,e.g., lubricating agents such as magnesium stearate. In the case ofcapsules, tablets, and pills, the dosage forms may also comprisebuffering agents and can additionally be prepared with enteric coatings.

Preparation of a compound of the invention in solid dosage form mayvary. For example, in one embodiment, a liquid or gelatin formulationmay be prepared by combining a compound, such as those described above,and adding a thickening agent to the liquid mixture to form a gelatin.The gelatin may then be encapsulated in unit dosage form to form acapsule. In another exemplary embodiment, an oily preparation of acompound prepared as described above may be lyophilized to for a solidthat may be mixed with one or more pharmaceutically acceptableexcipient, carrier or diluent to form a tablet.

Further embodiments which may be useful for oral administration of acompound for the invention include liquid dosage forms. In suchembodiments, a liquid dosage may include a pharmaceutically acceptableemulsion, solution, suspension, syrup, and elixir containing inertdiluents commonly used in the art, such as water. Such compositions mayalso comprise adjuvants, such as wetting agents, emulsifying andsuspending agents, and sweetening, flavoring, and perfuming agents.

In still further embodiments, the compounds described herein can beformulated as a depot preparation. Such long acting formulations can beadministered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Depot injections can beadministered at about 1 to about 6 months or longer intervals. Thus, forexample, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Experimental Section

Scheme 1 shows a general methodology for the synthesis of1H-benzo[d]imidazol-2-yl amides 1.5. An appropriately substituted1-fluoro-2-nitrobenzene 1.1 is reacted with a primary amine to afford1-amino-2-nitrobenzene 1.2. Alternatively, a 1-chloro-2-nitrobenzene isreacted with a primary amine under palladium catalysis to provide thedesired 1-amino-2-nitrobenzene 1.2. The nitro group may be reduced tothe corresponding amine by a variety of well-established methods toprovide 1,2-diaminobenzenes 1.3. Reaction of 1.3 with cyanogen bromideaffords 1H-benzo[d]imidazol-2-amines 1.4. Amide coupling with either anappropriate carboxylic acid or acyl chloride can afford1H-benzo[d]imidazol-2-yl amides such as 1.5.

TABLE 1 List of Examples with Molecular Weight Data Example StructureName Molecular Weight 330

N-(1-(tert-butyl)-7-cyano-5-fluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 384.4 331

N-(1-cyclobutyl-6-(difluoromethoxy)-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 369.4 332

N-(1-(3,3-difluorocyclobutyl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide379.5 333

N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl- 3-methylbutanamide 392.4334

N-(1-cyclobutyl-7-fluoro-6-(2,2,2-trifluoroethoxy)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide 401.4335

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 419.5 336

(R)-N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3- phenylbutanamide 391.5 337

N-(6-cyano-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 324.4 338

3-cyclopropyl-N-(6-(difluoromethoxy)-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-methylbutanamide 409.5 339

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3-(3-fluorophenyl)-3- hydroxybutanamide,stereoisomer 1 412.4 340

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 396.4341

N-(6-cyano-1-neopentyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 390.5 342

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- bis(methyl-d3)butanamide 370.5 343

N-(6-bromo-1-cyclobutyl-4-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 382.3 344

N-(6-cyano-1-(cyclopropylmethyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 2 374.4 345

N-(6-cyano-1-cyclobutyl-7-fluoro-1H-benzo[d]imidazol-2-yl)-5,5,5-trifluoro-3,3- dimethylpentanamide 396.4346

N-(6-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide365.4 347

N-(5-chloro-6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 408.9 348

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-3- hydroxybutanamide,stereoisomer 1 412.4 349

N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 402.4 350

N-(6-cyano-1-cyclobutyl-5-fluoro-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 392.4 351

N-(6-(difluoromethoxy)-7-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-methylbutanamide 385.4 352

N-(1-cyclobutyl-4-fluoro-6-(1- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 427.4 353

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide 413.4354

N-(1-(tert-butyl)-6-cyano-1H- benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide 338.5 355

N-(4-fluoro-6-methoxy-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 347.4 356

N-(6-cyano-1-cyclobutyl-5,7-difluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 346.4 357

N-(1-cyclobutyl-5,7-difluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 321.4 358

N-(1-cyclobutyl-7-methoxy-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 2 379.5 359

N-(1-cyclobutyl-4-fluoro-6-hydroxy-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 373.4 360

N-(7-acetyl-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 2423.5 361

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 378.4 362

N-(1-cyclobutyl-5,7-difluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide379.5 363

N-(1-cyclobutyl-6-(difluoromethoxy)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 395.4 364

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-4,4-difluoro-3,3- dimethylbutanamide 366.4 365

(S)-N-(1-(3,3-difluorocyclobutyl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-2,3,3-trimethylbutanamide393.5 366

N-(6-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 419.4 367

3-cyclopropyl-N-(6-(difluoromethoxy)-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-methylbutanamide 409.5 368

N-(1-(tert-butyl)-6-(difluoromethoxy)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 397.4 369

(S)-N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3- phenylbutanamide 391.5 370

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4-fluoro-3- (fluoromethyl)-3-methylbutanamide379.5 371

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 2 419.5 372

(S)-N-(1-(tert-butyl)-6-cyano-4-fluoro-1H- benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropane-1-carboxamide 328.4 373

N-(6-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)- 3-hydroxybutanamide,stereoisomer 2 424.5 374

N-(6-(difluoromethoxy)-7-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 2 447.5 375

N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 2388.5 376

N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 427.4 377

N-(4-chloro-6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 344.8 378

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 384.4 379

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 350.5 380

N-(1-cyclobutyl-7-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- methylbutanamide 371.4 381

N-(6-cyano-4-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide390.4 382

N-(6-bromo-1-cyclobutyl-4-methoxy-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 394.3 383

(S)-N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 2,3,3-trimethylbutanamide371.5 384

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2,6-difluorophenyl)- 3-hydroxybutanamide,stereoisomer 2 424.5 385

N-(1-cyclobutyl-4,7-difluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 433.4 386

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4-difluoro-3,3- dimethylbutanamide 379.5 387

N-(1-(tert-butyl)-6-cyano-7-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 330.4 388

N-(6-(benzyloxy)-1-cyclobutyl-4-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 409.5 389

N-(1-cyclobutyl-6-(difluoromethoxy)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 351.4 390

N-(1-cyclobutyl-6-(difluoromethoxy)-4-fluoro-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 395.4 391

N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide 355.5 392

N-(6-bromo-4-methoxy-1-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 408.3 393

N-(1-(tert-butyl)-6-(difluoromethoxy)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 353.4 394

N-(1-cyclobutyl-6-fluoro-7-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 347.4 395

N-(7-bromo-1-cyclobutyl-6-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 382.3 396

N-(6-cyano-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1402.4 397

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- bis(methyl-d3)butanamide 370.5 398

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 413.4 399

N-(6-chloro-1-cyclobutyl-7-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 363.9 400

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 431.4 401

N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 366.4 402

N-(1-cyclobutyl-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1415.4 403

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1- methylcyclopropyl)acetamide 359.4404

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 409.5 405

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide 431.4 406

3-cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-3-methylbutanamide 397.4 407

(S)-N-(6-(2-hydroxypropan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)- 2,3,3-trimethylbutanamide385.4 408

N-(1-cyclobutyl-7-fluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 357.4 409

N-(6-(difluoromethoxy)-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3-hydroxy-3-phenylbutanamide 501.4 410

(S)-N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3-phenylbutanamide 409.5411

N-(6-cyano-1-cyclobutyl-4-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 328.4 412

(R)-N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3-phenylbutanamide 409.5413

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2- ((trifluoromethyl)thio)acetamide405.4 414

3,3-dimethyl-N-(4,5,6-trichloro-1-cyclobutyl-7-methoxy-1H-benzo[d]imidazol-2- yl)butanamide 418.7 415

N-(4,6-dichloro-1-cyclobutyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- methylbutanamide 386.3 416

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 400.4 417

N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 303.4 418

N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1417.5 419

N-(6-cyano-4-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 444.4 420

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 330.4 421

N-(1-cyclobutyl-4-fluoro-6-(1- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 373.5 422

N-(1-cyclobutyl-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 2415.4 423

N-(6-(difluoromethoxy)-7-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4-fluoro-3-(fluoromethyl)-3- hydroxybutanamide 421.4 424

N-(1-cyclobutyl-5,7-difluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide391.5 425

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide355.5 426

N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 350.5 427

N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 379.5 428

N-(6-cyano-1-(cyclopropylmethyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 374.4 429

N-(1-cyclobutyl-7-fluoro-6-methoxy-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 333.4 430

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2,4-difluorophenyl)- 3-hydroxybutanamide,stereoisomer 1 424.5 431

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3,3-dimethylbutanamide394.4 432

N-(1-cyclobutyl-6-(3-fluorooxetan-3-yl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 359.4 433

4,4,4-trifluoro-N-(4-fluoro-6-methoxy-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide401.4 434

3-cyclopropyl-N-(6-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3-methylbutanamide 391.5435

2-(3-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)acetamide 395.5 436

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 342.4 437

N-(6-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 342.4 438

N-(1-cyclobutyl-4,7-difluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide379.5 439

N-(6-chloro-7-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 344.8 440

N-(6-(2-hydroxypropan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 371.4441

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1406.5 442

N-(1-cyclobutyl-7-methoxy-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 379.5 443

(S)-N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-2,3,3-trimethylbutanamide375.5 444

N-(1-(tert-butyl)-6-cyano-7-fluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 384.4 445

N-(1-cyclobutyl-6-(1-cyclopropyl-1-hydroxyethyl)-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide387.5 446

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 413.4 447

methyl 2-(1-cyclobutyl-2-(3,3- dimethylbutanamido)-6-fluoro-1H-benzo[d]imidazol-7-yl)acetate 375.4 448

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-bis(methyl- d3)butanamide 352.5 449

N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 303.4 450

N-(1-cyclobutyl-5-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide411.5 451

N-(1-cyclobutyl-7-fluoro-6-(1- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 373.5 452

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-3-hydroxybutanamide, stereoisomer 1 392.4 453

N-(1-cyclobutyl-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 375.3 454

N-(1-cyclobutyl-6-(dimethylamino)-7-fluoro-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 346.5 455

(S)-N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2- yl)-2,3,3-trimethylbutanamide369.5 456

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4-difluoro- 3,3-dimethylbutanamide397.4 457

N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 348.4 458

N-(1-cyclobutyl-7-methoxy-1H- benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide 341.5 459

N-(6-(difluoromethoxy)-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide383.4 460

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2,4-difluorophenyl)- 3-hydroxybutanamide,stereoisomer 2 424.5 461

N-(6-(difluoromethoxy)-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 437.4 462

N-(7-bromo-1-cyclobutyl-6-fluoro-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-methylbutanamide 384.2 463

N-(6-(difluoromethoxy)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide, stereoisomer 1 429.5 464

N-(6-cyano-1-cyclobutyl-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 372.4 465

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 2406.5 466

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 431.4 467

N-(6-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2,6-difluorophenyl)- 3-hydroxybutanamide,stereoisomer 1 424.5 468

N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1388.5 469

N-(1-cyclobutyl-4-fluoro-6-methoxy-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 333.4 470

N-(1-cyclobutyl-5,7-difluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 433.4 471

N-(6-cyano-1-((1-methylcyclopropyl)methyl)-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1388.5 472

N-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide 381.5 473

N-(7-cyano-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 324.4 474

N-(4-fluoro-6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide 373.5 475

N-(1-cyclobutyl-6-(3,3-difluoroazetidin-1-yl)-7-fluoro-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 394.4 476

N-(1-cyclobutyl-7-methoxy-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 315.4 477

N-(6-bromo-1-cyclobutyl-4-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 432.3 478

N-(6-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)- 3-hydroxybutanamide,stereoisomer 1 424.5 479

N-(1-cyclobutyl-6-(1,3-difluoro-2- hydroxypropan-2-yl)-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 397.4 480

4-fluoro-N-(4-fluoro-6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-(fluoromethyl)-3-methylbutanamide 411.5 481

N-(7-fluoro-6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide375.5 482

N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 356.4 483

N-(6-cyano-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-3- hydroxybutanamide,stereoisomer 1 420.4 484

N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro- 3,3-dimethylbutanamide420.4 485

N-(1-cyclobutyl-6-(dimethylamino)-7-fluoro-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- phenylbutanamide, stereoisomer 1410.5 486

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 396.4487

N-(1-cyclobutyl-6-(1-hydroxycyclobutyl)-7-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide439.5 488

N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 436.3 489

N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 423.5 490

N-(1-cyclobutyl-6-(1-hyd roxycyclobutyl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide423.5 491

N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide 427.4 492

4,4,4-trifluoro-N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide, stereoisomer 1 425.5 493

N-(6-cyano-1-(1-methylcyclobutyl)-7-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 478.4 494

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 408.4 495

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 342.4 496

N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 418.3 497

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 427.4 498

N-(6-cyano-1-cyclobutyl-7-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 394.4 499

N-(5,6-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 405.3 500

N-(4-fluoro-6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 445.4 501

N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-7-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide427.5 502

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-(2,2-difluoroethyl)cyclopropane-1-carboxamide 395.4 503

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 2 408.4 504

N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 430.4 505

2-(2,4-difluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)acetamide 413.5 506

N-(1-(tert-butyl)-6-cyano-4-methoxy-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 412.4 507

N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 378.4 508

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 2 427.4 509

N-(1-(tert-butyl)-6,7-difluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 393.3 510

N-(1-(tert-butyl)-6-cyano-4-methoxy-1H-benzo[d]imidazol-2-yl)bicyclo[2.1.1]hexane-1- carboxamide 352.4 511

2-(bicyclo[1.1.1]pentan-1-yl)-N-(6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)acetamide 367.5 512

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 412.4 513

N-(6,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 405.3 514

N-(1-(tert-butyl)-6-cyano-4-methoxy-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide 412.4515

N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-2,3,3-trimethylbutanamide, stereoisomer 1 429.5 516

N-(1-cyclobutyl-7-(trifluoromethoxy)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 369.4 517

N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide360.4 518

N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-methyl-3-(pyridin-2- yl)butanamide 373.5 519

N-(4-fluoro-6-(2-hydroxypropan-2-yl)-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 445.4 520

N-(1-(tert-butyl)-6-cyano-4-methoxy-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)acetamide 394.4 521

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-bis(methyl- d3)butanamide 351.5 522

N-(5,7-difluoro-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)acetamide 387.4 523

N-(5,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 405.3 524

4,4-difluoro-N-(5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide353.4 525

N-(5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 387.4 526

N-(5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 387.4 527

N-(5-fluoro-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)acetamide 369.4 528

N-(1-(tert-butyl)-5-fluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 375.3 529

N-(1-(tert-butyl)-5-fluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 375.3 530

N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 377.4 531

N-(1-(tert-butyl)-5,7-difluoro-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)acetamide 375.3 532

N-(1-(tert-butyl)-5,7-difluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 393.3 533

N-(5,6-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4-difluoro-3,3- dimethylbutanamide 371.4 534

N-(5,6,7-trifluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1- (trifluoromethyl)cyclopropyl)acetamide405.3 535

N-(1-(tert-butyl)-6-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 409.8 536

N-(7-cyano-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 412.4 537

N-(7-cyano-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 412.4 538

N-(5,6-difluoro-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)acetamide 387.4 539

N-(6-chloro-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 421.8 540

N-(5,6-difluoro-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 401.4 541

N-(7-cyano-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 368.5 542

N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 430.4 543

N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 2 426.4 544

N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)- 2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 426.4 545

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 412.4 546

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 412.4 547

N-(7-cyano-5-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3- methylbutanamide 368.5 548

N-(7-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 2 412.4 549

N-(7-bromo-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3- tetrafluorocyclobutyl)acetamide,stereoisomer 1 466.3 550

N-(7-bromo-6-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 396.3 551

N-(6-cyano-1-(4-fluorophenyl)-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 420.3 552

N-(1-cyclobutyl-6-fluoro-7-vinyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide 329.4 553

N-(6-cyano-4-methoxy-1-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 424.4 554

N-(6-cyano-4-methoxy-1-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide 408.4 555

N-(6-chloro-7-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide 405.8556

N-(6-chloro-7-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)propanamide, stereoisomer 1 417.8 557

N-(1-(tert-butyl)-5,6-difluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 393.3 558

N-(1-(tert-butyl)-5,6-difluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 1 393.3 559

2-(2,2,3,3-tetrafluorocyclobutyl)-N-(5,6,7-trifluoro-1-(1-methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)acetamide,stereoisomer 2 423.3 560

N-(1-(tert-butyl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, stereoisomer 2 393.3 561

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-2-(1- (trifluoromethyl)cyclopropyl)acetamide394.4 562

N-(6-cyano-4-fluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro- 2,3,3-trimethylbutanamide,stereoisomer 1 410.4

Biological Assay Methods

Kv7.2/7.3 Activation Assay

The ability of compounds to potentiate K-currents in Kv7.2/7.3containing HEK cells was assessed using planar patch-clamp on the QPatchautomated screening platform.

Cell Line: The hKv7.2/7.3 cell line was obtained from Chantest(Cleveland, OH 44128) cat. #CT6147. These HEK cells will express theKv7.2/7.3 ion channels when induced.

Cell Culture: Cells were maintained in a media containing DMEM/F12;50/50 (GIBCO cat. #11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.#26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat. #15140), 0.005mg/mL Blasticidin (INVIVOGEN cat. #ant-bl-1), 0.5 mg/mL Geneticin (GIBCOcat. #10131), 0.1 mg/mL Zeocin (GIBCO cat. #R25001). Cells used in theelectrophysiology assay were maintained in a media without Blasticidin,Geneticin and Zeocin for 2 days and channel expression was induced byadding tetracycline (BIOLINE cat. #BIO-87030) at a final concentrationof 1 mg/mL. Cells were grown in T-175 flask to ˜₇₅% confluency. Currentswere recorded 24 hours after channel induction.

Compound Plates: Test compounds were prepared by performing serialdilutions on a Biomek NX (BECKMAN COULTER). Final dilutions were made inexternal recording solution with a final DMSO concentration of 0.1%DMSO. For single concentration screens each plate had 10 μM retigabineas a positive control and 0.1% DMSO as a negative control.

Electrophysiology: On the day of the experiment cells were washed withHank's Balanced Salt Solution (HBBS) (GIBCO cat. #14175) and harvestedwith Tryple (GIBCO cat. #12604). Cells were then centrifuged at 2000 rpmfor 5 minutes and resuspended in CHO—S-SFM (GIBCO cat. #12052) at ˜3×10⁶cells/mL. Cells were stirred for 30 minutes before experiments werestarted. External recording solution contained (in mM): NaCl (145), KCl(4), CaCl₂) (2), MgCl₂ (1), HEPES (10) and Glucose (10); pH was adjustedto 7.4 with NaOH and the osmolarity was adjusted to 300-305 mOsM withsucrose if necessary. Internal solution contained (in mM): KCl (125), KF(10), EGTA (5), Na₂ATP (5), MgCl₂ (3.2), HEPES (5); pH was adjusted to7.2 with KOH and the osmolarity was adjusted to 298-302 mOsM withsucrose.

Potassium channel activity was measured on the QPatch HTX (SophionBioscience) using QPlates with 48-wells/plate. Each cell was taken as anindependent experiment and only one compound was tested per well.Potassium channel activity was elicited by holding at −80 mV andstepping to −30 mV for 2 s followed by a 100 ms pulse to −120 mV.

Single concentration screen: Baseline conditions were obtained byrecording 5 sweeps in the external solution only, this was repeated forthree applications of the external solution. The effect of testcompounds on elicited current was then assessed by recording 5 sweeps inthe presence of a 3 μM compound solution. The steady-state current atthe end of the 2 s pulse to −30 mV was measured to determine the foldincrease from baseline.

Data of the Kv7.2/7.3 Activation Assay is summarized in Table 2

TABLE 2 Kv7.2/7.3 QPatch Single Concentration Screen Results. HPLCRetention MS (ESI) m/z Kv7.2/7.3 Example time (min)^(a) (M + H)⁺Activity^(b) 330 3.5 383.2 (M − H)− ++ 331 3.8 370.4 +++ 332 3.1 380.4 +333 4.0 393.2 ++ 334 3.9 402.4 ++ 335 2.9 420.4 O 336 2.9 392.4 + 3373.7 325.2 ++ 338 4.1 410.4 +++ 339 3.4 413.2 O 340 4.0 397.2 + 341 3.7391.2 + 342 3.1 371.2 +++ 343 4.1 382.0 +++ 344 3.4 375.2 + 345 3.9397.2 + 346 3.7 366.4 ++ 347 3.5 409.2 + 348 3.4 413.2 O 349 3.8 403.2++ 350 3.5 393.2 + 351 3.2 386.4 + 352 3.6 428.4 ++ 353 2.9 414.4 + 3543.9 339.2 ++ 355 3.6 348.4 +++ 356 3.8 347.2 + 357 3.9 322.4 +++ 358 3.3380.4 + 359 3.2 374.4 ++ 360 3.6 424.4 O 361 4.1 379.2 ++ 362 3.4 380.4++ 363 3.8 396.4 + 364 3.4 367.2 ++ 365 3.3 394.4 + 366 4.3 420.4 + 3674.0 410.4 ++ 368 3.9 398.4 + 369 2.9 392.4 O 370 2.6 380.4 ++ 371 2.9420.4 O 372 3.3 329.2 ++ 373 3.8 425.2 ++ 374 3.8 448.4 ++ 375 3.6389.2 + 376 3.3 428.4 + 377 3.7 345.2 +++ 378 3.6 385.2 +++ 379 3.9351.2 ++ 380 3.4 372.4 + 381 3.8 391.2 ++ 382 3.8 394.0 +++ 383 2.9372.4 ++ 384 3.6 425.2 ++ 385 3.7 434.4 O 386 2.7 380.4 + 387 3.5 331.2++ 388 4.1 410.4 +++ 389 3.3 352.4 ++ 390 4.0 396.4 + 391 2.6 356.4 +392 4.0 408.0 +++ 393 3.8 354.4 +++ 394 4.0 348.4 O 395 4.2 383.2 O 3963.4 403.2 + 397 3.1 371.2 +++ 398 3.1 414.4 + 399 4.3 364.4 +++ 400 3.3432.4 +++ 401 3.7 367.2 ++ 402 3.5 416.4 ++ 403 3.0 360.4 ++ 404 3.8410.4 + 405 3.1 432.4 ++ 406 3.3 398.4 +++ 407 3.4 386.4 ++ 408 4.3358.4 ++ 409 4.3 502.4 + 410 3.3 410.4 O 411 3.6 329.2 +++ 412 3.3 410.4++ 413 3.6 406.0 +++ 414 4.5 418.0 (M − H)− ++ 415 3.5 384.0 (M − H)− O416 3.4 401.2 ++ 417 3.2 304.4 ++ 418 3.7 418.4 ++ 419 3.9 445.2 + 4203.4 331.2 + 421 3.3 374.4 +++ 422 3.5 416.4 + 423 3.5 422.4 + 424 3.6392.4 O 425 3.0 356.4 ++ 426 3.9 351.2 +++ 427 4.0 380.4 ++ 428 3.4375.2 ++ 429 3.5 334.4 +++ 430 3.9 425.2 ++ 431 3.7 395.2 ++ 432 3.2360.4 +++ 433 3.9 402.4 ++ 434 3.9 392.4 +++ 435 3.1 396.4 O 436 3.8343.2 ++ 437 3.8 343.2 ++ 438 3.6 380.4 O 439 3.9 345.2 + 440 3.1372.4 + 441 3.6 407.2 ++ 442 3.3 380.4 + 443 3.3 376.4 ++ 444 3.7 385.2++ 445 3.4 388.4 ++ 446 3.1 414.4 ++ 447 3.6 376.4 +++ 448 2.6 353.6 ++449 3.2 304.4 ++ 450 3.8 412.4 + 451 3.3 374.4 O 452 3.5 393.2 O 453 4.2376.0 ++ 454 3.0 347.2 +++ 455 3.3 370.4 ++ 456 3.2 398.4 ++ 457 3.6349.2 ++ 458 3.6 342.4 +++ 459 4.0 384.4 +++ 460 3.9 425.2 ++ 461 4.2438.4 + 462 3.3 385.2 ++ 463 3.6 430.4 + 464 4.0 373.2 ++ 465 3.6 407.2++ 466 3.3 432.4 ++ 467 3.6 425.2 + 468 3.6 389.2 + 469 3.4 334.4 +++470 3.8 434.4 + 471 3.6 389.2 + 472 3.2 382.4 +++ 473 3.7 325.2 ++ 4743.1 374.4 O 475 3.8 395.4 ++ 476 3.0 316.4 + 477 4.4 432.0 +++ 478 3.8425.2 + 479 3.2 398.4 ++ 480 3.2 412.4 O 481 3.4 376.4 O 482 3.6 357.2+++ 483 3.5 421.2 ++ 484 4.0 421.2 + 485 3.1 411.2 +++ ^(a)HPLC Method B^(b)Increase over baseline in current from Kv7.2/Kv7.3 co-expressing HEKcells, using Kv7.2/7.3 Activation Assay as described in Biological AssayMethods section, measured at compound concentration of 3 μM described asa range from 1.2-2.9 (+), 3-3.9 (++), and >4 (+++) fold increase overbaseline; O represents open channel at holding potential.

The Thallium Flux Assay is used as a surrogate indicator of potassiumchannel activity.

The experimental protocol was adapted from the FluxOR™ II GreenPotassium Ion Channel Assay User Guide (Pub. No. MAN0016084,Invitrogen). Conditions were optimized for the Kv7.2/7.3 cell line.

Cell Line: The hKV7.2/7.3 cell line was obtained from Chantest(Cleveland, OH 44128) cat. #CT6147.

Cell Culture: Kv7.2/7.3 cells were maintained in a media containingDMEM/F12; 50/50 (GIBCO cat. #11330), 10% Fetal Bovine Serum (FBS) (GIBCOcat. #26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat. #15140),0.005 mg/ml Blasticidin (SIGMA 15205), 0.5 mg/mL Geneticin (GIBCO cat.#10131), and 0.1 mg/mL Zeocin (GIBCO cat. #R25001). One day prior toexperimentation, cells were plated in 96 well clear bottom plates(Corning cat. #353219) in a media without Blasticidin, Geneticin, orZeocin. Channel expression was induced by adding tetracycline (Biolinecat. #BIO87030) at a final concentration of 10 ng/mL.

Compound Plates: The test compound is diluted in a mixture of 0.1%DMSO/extracellular solution with an eight-point concentration range from0.014 μM to 30 μM. Serial dilutions were made on a Biomek NXP (BECKMANCOULTER).

Measurement and data analysis: A plate reader (Enspire, Perkin Elmer) isused to characterize the ion-channel modulating properties of novelcompounds using an excitation wavelength of 475 nm and an emissionwavelength of 530 nm. After a 15 sec baseline measurement, the stimulusbuffer containing thallium and potassium is injected. A final endpointmeasure is taken after 90 sec. Responses are normalized to positivecontrol (retigabine, 30 μM max). Mean normalized responses at eachconcentration tested are fit to the standard Hill equation to generatean EC50 and maximal response.

Data of the Thallium Flux Assay is summarized in Table 3

TABLE 3 Kv7.2/7.3 Thallium Flux Assay Results. HPLC Retention MS (ESI)m/z Kv7.2/7.3 Example time (min)^(a) (M + H)⁺ Activity^(c) 486 3.8 397.2*** 487 4.0 440.4 *** 488 3.8 437.2 *** 489 3.8 424.4 *** 490 4.0 424.4*** 491 3.4 428.4 *** 492 3.8 426.4 *** 493 4.1 479.2 *** 494 3.8 409.2*** 495 3.6 343.2 *** 496 3.6 419.2 *** 497 3.5 428.4 *** 498 4.0 395.2*** 499 3.9 406.0 *** 500 3.4 446.4 *** 501 3.7 428.4 ** 502 3.9 396.4 *503 3.9 409.2 *** 504 3.7 431.2 *** 505 3.3 414.4 *** 506 3.6 413.2 ***507 4.0 379.2 *** 508 3.5 428.4 ** 509 3.6 394.4 *** 510 3.4 353.2 **511 2.7 368.4 *** 512 3.6 413.2 *** 513 4.0 406.0 *** 514 3.6 413.2 ***515 3.6 430.4 *** 516 4.3 370.4 *** 517 3.8 361.2 *** 518 2.4 374.4 **519 3.4 446.4 *** 520 3.6 395.2 * 521 3.6 352.4 *** 522 4.1 388.4 ***523 4.1 406.4 *** 524 3.9 354.4 *** 525 4.0 388.4 *** 526 4.0 388.4 ***527 4.1 370.4 *** 528 3.9 376.4 *** 529 3.9 376.4 *** 530 3.9 378.4 ***531 3.7 376.4 *** 532 3.7 394.4 *** 533 3.9 372.4 *** 534 4.0 406.4 ***535 4.1 410.0 *** 536 3.7 413.2 *** 537 3.7 413.2 *** 538 4.0 388.4 ***539 4.2 422.0 *** 540 4.4 402.4 *** 541 3.9 369.2 *** 542 3.7 431.2 ***543 3.9 427.2 *** 544 3.9 427.2 *** 545 3.8 413.2 *** 546 3.8 413.2 ***547 4.0 369.2 *** 548 3.6 413.2 *** 549 4.1 466.0 *** 550 4.1 396.0 ***551 3.6 421.4 *** 552 3.8 330.4 *** 553 3.7 425.2 *** 554 4.0 409.2 ***555 4.6 406.0 *** 556 4.8 418.0 *** 557 3.8 394.4 *** 558 3.8 394.4 **559 4.0 424.0 *** 560 3.6 394.4 *** 561 3.5 395.2 *** 562 3.9 411.2 ***^(a)HPLC Method B ^(c)Measured EC50 of Kv7.2/Kv7.3 activation usingthallium flux assay as described in Biological Assay Methods section,described as a range from 3-10 μM (*), 1-3 μM (**), and <1 μM (***).

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

Kv7 Activators and Methods of Treating ALS

In embodiments, this disclosure relates to methods for treatingneurodegenerative disease, such as amyotrophic lateral sclerosis, in asubject in need thereof comprising: administering to the subject atherapeutically effective amount of a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,wherein the neurodegenerative disease is treated.

In embodiments, the subject is a subject with definite ALS, hasamyotrophic lateral sclerosis symptom onset duration of less than about18 months, plasma creatinine levels of about 72 μM/L or greater,concomitant riluzole administration, concomitant dexpramipexoleadministration, and combinations thereof.

It has been demonstrated that the motor neurons of ALS patients havereduced delayed-rectifier potassium current amplitudes, which mayunderlie the hyperexcitability seen in these diseased neurons.Embodiments described herein are directed to compounds of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, which activate Kv7 channels to block the hyperexcitabilityassociated with ALS and improve motor neuron function and/or survival.

Embodiments are directed to methods for treating neurodegenerativedisease in a subject comprising administering to the subject atherapeutically effective amount of a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,wherein the neurodegenerative disease is treated. The compounds offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, may be administered to any individualexhibiting the symptoms of a neurodegenerative disease or to individualspredisposed to a neurodegenerative disease. Non-limiting examples ofneurodegenerative diseases that may be treated using a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, include amyotrophic lateral sclerosis (ALS),Huntington's disease, metabolically induced neurological damage,Alzheimer's disease, Pick's disease, senile dementia, age associatedcognitive dysfunction, vascular dementia, multi-infarct dementia, Lewybody dementia, neurodegenerative dementia, frontotemporal dementia(FTD), familial FTD, neurodegenerative movement disorder, ataxia,Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy,primary lateral sclerosis, seizure disorders, motor neuron disorder ordisease, inflammatory demyelinating disorder, Parkinson's disease,hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, orany combination thereof.

Embodiments are directed to methods for treating neurodegenerativedisease, such as amyotrophic lateral sclerosis, in a subject in needthereof comprising: administering to the subject a therapeuticallyeffective amount of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, wherein theneurodegenerative disease is treated. In embodiments, the subject is asubject with definite ALS, has amyotrophic lateral sclerosis symptomonset duration of less than about 18 months, plasma creatinine levels ofabout 72 μM/L or greater, concomitant riluzole administration,concomitant dexpramipexole administration, and combinations thereof.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject in need thereof comprising: administering to thesubject a therapeutically effective amount of a compound of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, wherein the amyotrophic lateral sclerosis is treated.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject diagnosed with definite amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, wherein theamyotrophic lateral sclerosis is treated. In embodiments, the definiteamyotrophic lateral sclerosis is as defined by the El Escorial diagnosiscriteria. In embodiments, the subject is a subject with definite ALS,amyotrophic lateral sclerosis symptom onset duration of less than about18 months, plasma creatinine levels of about 72 M/L or greater,concomitant riluzole administration, concomitant dexpramipexoleadministration, and combinations thereof.

Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is aprogressively debilitating motor neuron disease, characterized bydegeneration and dysfunction/death of upper and lower motor neurons. ALSis universally fatal but the rate of disease progression may not belinear.

In accordance with embodiments described herein, the El Escorial WorldFederation of Neurology's Criteria for the Diagnosis of ALS is asfollows (See also Brooks, B. R., R. G. Miller, et al. (2000). “ElEscorial revisited: revised criteria for the diagnosis of amyotrophiclateral sclerosis.” Amyotrophic Lateral Sclerosis Other Motor NeuronDisord 1(5): 293-9, which is incorporated by reference in its entirety).As used in the El Escorial World Federation of Neurology's Criteria forthe Diagnosis of ALS, the term “definite” is intended to mean specificclinical exclusionary criteria met, no other diagnosis possible on basisof clinical distribution or laboratory findings; the term “dementia” isintended to mean progressive deterioration of specific cognitivefunctions; the term “onset” is intended to mean time of first subjectivesymptom noticed by patient which later is confirmed by examination; theterm “possible” is intended to mean specific clinical and exclusionarycriteria met; the term “probable” is intended to mean specific clinicaland exclusionary criteria; and the term “worsening” is intended to meanincreased weakness of muscles in a previously affected segment or newweakness in a previously unaffected segment.

The diagnoses of ALS requires the presence of: 1) signs of lower motorneuron (LMN) degeneration by clinical, electrophysiological orneuropathologic examination, 2) signs of upper motor neuron (UMN)degeneration by clinical examination, and 3) progressive spread of signswithin a region or to other regions, together with the absence ofelectrophysiological evidence of other disease processes that mightexplain the signs of LMN and/or UMN degenerations; and neuroimagingevidence of other disease processes that might explain the observedclinical and electrophysiological signs.

Furthermore, the El Escorial World Federation of Neurology's Criteriafor the Diagnosis of ALS set forth the following steps in the diagnosisof Amyotrophic Lateral Sclerosis. The diagnoses of ALS is made possibleby 1) history, physical and appropriate neurological examinations toascertain clinical finding which may suggest suspected, possible,probable or definite ALS, 2) electrophysiological examinations toascertain findings which confirm LMN degeneration in clinically involvedregions, identify LMN degeneration in clinically uninvolved regions andexclude other disorders, 3) neuroimaging examinations to ascertainfindings which may exclude other disease processes, 4) clinicallaboratory examinations, determined by clinical judgment, to ascertainpossible ALS-related syndromes, 5) neuropathologic examinations, whereappropriate, to ascertain findings which may confirm or exclude sporadicALS, coexistent sporadic ALS, ALS-related syndromes or ALS variants, 6)repetition of clinical and electrophysiological examinations at leastsix months apart to ascertain evidence of progression.

Definite ALS is defined on clinical grounds alone by the presence of UMNas well as LMN signs in the bulbar region and at least two of the otherspinal regions or the presence of UMN and LMN signs in three spinalregions. The important determinants of diagnosis of definite ALS in theabsence of electrophysiological, neuroimaging and laboratoryexaminations are the presence of UMN and LMN signs together in multipleregions.

Probable ALS is defined on clinical grounds alone by UMN and LMN signsin at least two regions. While the regions may be different, some UMNsigns must be rostral (above) the LMN signs. Multiple differentcombinations of UMN and LMN signs may be present in patients withprobable ALS.

Possible ALS is defined on clinical grounds alone when the UMN and LMNsigns are in only one region or UMN signs alone are present in 2 or moreregions or LMN signs are rostral to UMN signs (the latter distributionof signs needs to be differentiated from multiple non-ALS processes).Monomelic ALS, progressive bulbar palsy without spinal UMN and/or LMNsigns and progressive primary lateral sclerosis without spinal LMN signsand progressive primary lateral sclerosis without spinal LMN signsconstitute special cases which may develop LMN or UMN signs to meet thecriteria for probable ALS with time or be subsequently confirmed atautopsy by specific LMN and UMN neuropathologic findings.

Suspected ALS will manifest only LMN signs in 2 or more regions,although UMN pathology might be demonstrated at autopsy. However, onlyclinical signs are considered pertinent to this classification at thetime of diagnostic evaluation.

The clinical signs of progressive LMN and UMN degeneration seen in ALSmay 1) occur alone (sporadic ALS), 2) be present incidentally with otherpre-existing disease processes that have not developed in parallel withthe ALS (coexistent sporadic ALS), 3) Occur in association withlaboratory-defined or epidemiologically defined abnormalities that aretime-linked to the ALS (ALS-related syndromes), or 4) Occur inassociation with clinical, genetic or epidemiological features whichdevelop in parallel with the ALS (ALS variants).

The physical and neurological examinations will allow for the clinicaldiagnosis of ALS to a particular degree of certainty as defined above;however, the history of the disease onset, toxic exposures, past medicalhistory, injuries, family history, geographic location, etc., must beincorporated with the clinical examinations in determining whether thepatient may have an ALS related syndrome or an ALS variant.

ALS-related syndromes must meet the clinical, electrophysiological andneuroimaging criteria for possible, probable or definite ALS.ALS-related syndromes have unique laboratory-defined orepidemiologically defined features which are time-linked to thedevelopment of the ALS phenotype. If correction of the associatedlaboratory-defined feature does not result in correction of the ALSphenotype, then the patient with an ALS-related syndrome should beconsidered in the same way as a patient with sporadic ALS.

ALS-related syndromes include: 1) monoclonal gammopathy (monoclonalgammopathy of unknown significance, Waldenstroms's macroglobulinemia,osteosclerotic myeloma, etc.), 2) dysimmune motor system degeneration(autoimmune; high-titer GMI ganglioside antibody; etc.), 3) nonmalignantendocrine abnormalities (hyperthyroidism, hyperparathyroidism,hypogonadism, etc.), 4) lymphoma (Hodgkin's and non-Hodgkin's lymphoma).5) infection (HIV-1, HTLV-I, encephalitis lethargica, varicella-zoster,brucellosis, cat-scratch disease, Creutzfeldt-Jakob disease, syphilis,delayed post-poliomyelitis, etc.), 6) acquired enzyme defects(detoxification enzymes, etc.), 7) exogenous toxins (lead, mercury,arsenic, thallium, cadmium, manganese, aluminum, organic pesticides,lupin seeds, etc.), 8) physical injury (electric shock, radiationtherapy, etc.), 9) vascular (vasculitis; ischemic (Dejerine anteriorbulbar artery syndrome, etc.), 10) spondylotic myelopathy (painlessmyelopathy with no sensory signs, stabilization or progressionpost-surgery).

ALS Variants must meet the clinical, electrophysiological andneuroimaging criteria for possible, probable or definite ALS. Thepredominant presentation is that seen in sporadic ALS, but includes oneor more features such as: multiple phenotypes characterized by age ofonset; site of onset; length of survival; and presumed type ofinheritance.

Familial ALS variants in genetic linkage studies should be characterizedby an established genetic mode of inheritance over at least twogenerations and at least one clinically definite or autopsy confirmedcase and compelling evidence excluding other possible causes. Affectedsub pairs occurring in one generation alone may not result from a singlegene effect.

Examples: a) ALS with defined inheritance and known gene product(hexosaminidase A/B deficiency, superoxide dismutase deficiency); b) ALSwith defined inheritance and chromosome linkage but no gene product(chromosome 21 associated familial ALS or chromosome 2 associatedjuvenile familial ALS); c) ALS with defined inheritance and no knownlinkage or gene product (most cases or familial ALS); d) geographicclustering (including disorders seen in the Western Pacific, Guam, KiiPeninsula, North Africa, Madras, etc.); e) Eetrapyramidal signs(bradykinesia; cogwheel rigidity; tremor; clinically significant onsetof supranuclear eye signs (pursuit abnormalities); familial orsporadic); f) cerebellar degeneration (spinocerebellar abnormalities;familial or sporadic); g) dementia (progressive cognitive abnormalities;familial or sporadic); h) autonomic nervous system involvement(clinically significant abnormal cardiovascular reflexes; bowel orbladder control problems; familial or sporadic); i) objective sensoryabnormalities (decreased vibration; sharp-dull discrimination; bluntingof cold sensation; familial or sporadic); j) electrophysiologicalfeatures in the diagnoses of ALS

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, wherein the subject is selected from a subject with definiteamyotrophic lateral sclerosis, a subject with limb-onset amyotrophiclateral sclerosis, a subject with bulbar-onset amyotrophic lateralsclerosis, a subject with amyotrophic lateral sclerosis symptom onsetduration of less than about 18 months, a subject with a high level ofserum creatinine, a subject with low bicarbonate levels, a subject withconcomitant riluzole administration, a subject with concomitantdexpramipexole administration, and combinations thereof, and wherein theamyotrophic lateral sclerosis is treated. In certain embodiments, themethod further comprises monitoring said subject for any clinicalfeatures associated with amyotrophic lateral sclerosis. In certainembodiments, the method further comprises initiating therapy with atherapeutically effective amount of a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereofupon diagnosis of amyotrophic lateral sclerosis. In certain embodiments,the subject exhibits symptoms of amyotrophic lateral sclerosis. Incertain embodiments, the subject has definite amyotrophic lateralsclerosis, probable amyotrophic lateral sclerosis, possible amyotrophiclateral sclerosis or suspected amyotrophic lateral sclerosis.

In certain embodiments, the subject has upper motor neuron degenerationand lower motor neuron degeneration in the bulbar region and two otherspinal regions. In certain embodiments, the subject has upper motorneuron degeneration and lower motor neuron degeneration in three spinalregions. In certain embodiments, the subject is selected from a subjectwith symptom onset duration of less than about 18 months, a subject witha high level of serum creatinine, a subject with low levels of serumsodium bicarbonate, a subject with concomitant riluzole administration,a subject concomitant dexpramipexole administration, and combinationsthereof. In certain embodiments, a subject with a high level of serumcreatinine is a subject with greater than about 72 μmol/L serumcreatinine.

In embodiments, the subject with definite amyotrophic lateral sclerosisis a subject diagnosed with definite ALS as defined by the El Escorialcriteria. In certain embodiments, the subject with definite amyotrophiclateral sclerosis is a subject with upper motor neuron degeneration andlower motor neuron degeneration in the bulbar region and two otherspinal regions. In certain embodiments, the subject with definiteamyotrophic lateral sclerosis is a subject with upper motor neurondegeneration and lower motor neuron degeneration in three spinalregions.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject diagnosed with definite amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, wherein theamyotrophic lateral sclerosis is treated. In some embodiments definiteamyotrophic lateral sclerosis is the presence of the El Escorialdiagnosis criteria, amyotrophic lateral sclerosis symptom onset durationof less than about 18 months, limb-onset amyotrophic lateral sclerosis,plasma creatinine levels of about 72 μM/L or greater, concomitantriluzole administration, concomitant dexpramipexole administration, anALSFRS-R score of greater than 36.0, a pre-study progression rategreater than or equal to 0.8 points per month, a percentage predictedrelaxed (slow) vital capacity (SVC) of less than or equal to 102.0, anALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-Rbulbar domain score or greater than 9.0 points, an ALSFRS-R gross motordomain score of greater than 8.0 points, an abnormal neurological examof the tongue, an abnormal neurological exam of the pharynx, larynx andswallowing, an abnormal neurological exam of the lower extremities, anabnormal neurological exam of the upper extremities, an abnormalneurological exam of the triceps, an abnormal neurological exam of themuscle mass and bulk, an abnormal neurological exam of the bicep, anabnormal neurological exam, a pulse rate of greater than 81.0 beats perminute, a diastolic blood pressure of greater than 82.0 mmHg, a systolicblood pressure of less than or equal to 117.0 mmHg, a creatinine valueof greater than 72.0 μmol/L, a phosphorous value of less than or equalto 1.090 μmol/L, a platelet count of less than or equal to 248.0×10⁹cells/L, a cholesterol value of less than or equal to 5.3 mmol/L, alactate dehydrogenase value of less than or equal to 161.0 U/L, acreatine phosphokinase value of less than or equal to 184.0 U/L, abicarbonate value of less than or equal to 21.6 mmol/L, a triglyceridelevel of less than or equal to 1.4 mmol/L, a uric acid level of greaterthan 320.0 μmol/L, a gamma-glutamyltransferase (GGT) level of greaterthan 37.0 U/L, a total bilirubin level of less than or equal to 6.0μmol/L, a urine pH of less than or equal to 5.5, or any combinationthereof.

Embodiments are directed to methods for treating amyotrophic lateralsclerosis in a subject exhibiting symptoms of amyotrophic lateralsclerosis comprising administering to the subject a therapeuticallyeffective amount of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, wherein thesymptoms of amyotrophic lateral sclerosis are treated. In someembodiments, the subject exhibits clinical characteristics selected fromdefinite amyotrophic lateral sclerosis, amyotrophic lateral sclerosissymptom onset duration of less than about 18 months, limb-onsetamyotrophic lateral sclerosis, plasma creatinine levels of about 72 μM/Lor greater, concomitant riluzole administration, concomitantdexpramipexole administration, an ALSFRS-R score of greater than 36.0, are-study progression rate greater than or equal to 0.8 points per month,a percentage predicted relaxed (slow) vital capacity (SVC) of less thanor equal to 102.0, an ALSFRS-R fine motor domain score of greater than10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, anALSFRS-R gross motor domain score of greater than 8.0 points, anabnormal neurological exam of the tongue, an abnormal neurological examof the pharynx, larynx and swallowing, an abnormal neurological exam ofthe lower extremities, an abnormal neurological exam of the upperextremities, an abnormal neurological exam of the triceps, an abnormalneurological exam of the muscle mass and bulk, an abnormal neurologicalexam of the bicep, an abnormal neurological exam, a pulse rate ofgreater than 81.0 beats per minute, a diastolic blood pressure ofgreater than 82.0 mmHg, a systolic blood pressure of less than or equalto 117.0 mmHg, a creatinine value of greater than 72.0 μmol/L, aphosphorous value of less than or equal to 1.090 μmol/L, a plateletcount of less than or equal to 248.0×109 cells/L, a cholesterol value ofless than or equal to 5.3 mmol/L, a lactate dehydrogenase value of lessthan or equal to 161.0 U/L, a creatine phosphokinase value of less thanor equal to 184.0 U/L, a bicarbonate value of less than or equal to 21.6mmol/L, a triglyceride level of less than or equal to 1.4 mmol/L, a uricacid level of greater than 320.0 μmol/L, a gamma-glutamyltransferase(GGT) level of greater than 37.0 U/L, a total bilirubin level of lessthan or equal to 6.0 μmol/L, a urine pH of less than or equal to 5.5, orany combination thereof.

In certain embodiments, the subject with amyotrophic lateral sclerosissymptom onset duration of less than about 18 months is a subject withsymptom onset selected from less than 18 months, less than about 17months, less than about 16 months, less than about 15 months, less thanabout 14 months, less than about 13 months, less than about 12 months,less than about 11 months, less than about 10 months, less than about 9months, less than about 8 months, less than about 7 months, less thanabout 6 months, less than about 5 months, less than about 4 months, lessthan about 3 months, less than about 2 months, and less than about 1month. In certain embodiments, the subject with amyotrophic lateralsclerosis symptom onset duration of less than about 18 months is asubject with symptom onset selected from about 18 months, about 17months, about 16 months, about 15 months about 14 months, about 13months, about 12 months, about 11 months, about 10 months, about 9months, about 8 months, about 7 months, about 6 months, about 5 months,about 4 months, about 3 months, about 2 months, and about 1 month.

In certain embodiments, the subject with a high level of serumcreatinine is a subject with serum creatinine level selected fromgreater than about 40 μmol/L, greater than about 45 μmol/L, greater thanabout 50 μmol/L, greater than about 55 μmol/L, greater than about 60μmol/L, greater than about 65 μmol/L, greater than about 70 μmol/L,greater than about 72 μmol/L of serum creatinine. In certainembodiments, the subject with a high level of serum creatinine is asubject with serum creatinine level selected from about 40 μmol/L, about45 μmol/L, about 50 μmol/L, about 55 μmol/L, about 60 μmol/L, about 65μmol/L, about 70 μmol/L, about 72 μmol/L of serum creatinine.

In certain embodiments, the subject with concomitant riluzoleadministration is a subject on a stable dosing regimen of riluzole. Incertain embodiments, the subject with concomitant riluzoleadministration is a subject receiving about 50 milligrams of riluzoletwice daily. In certain embodiments, the subject with concomitantriluzole administration is a subject who has been receiving riluzole formore than about thirty days. In certain embodiments, the subject withconcomitant riluzole administration is a subject who has been receivingriluzole for about sixty days or more. In certain embodiments, thesubject with concomitant dexpramipexole administration is a subject on astable dosing regimen of dexpramipexole. In certain embodiments, thesubject with concomitant dexpramipexole administration is a subjectreceiving about 75 milligrams of dexpramipexole twice daily. In certainembodiments, the subject with concomitant dexpramipexole administrationis a subject receiving about 150 milligrams of dexpramipexole twicedaily. In certain embodiments, the subject with concomitantdexpramipexole administration is a subject receiving about 300milligrams of dexpramipexole twice daily.

In certain embodiments, treating amyotrophic lateral sclerosis in saidsubject is selected from improved ALSFRS-R score, improved CAFS rank,decreased mortality, increased life expectancy, and combinationsthereof. In some embodiments, the subject exhibits a greater than 20%improvement in ALS Functional Rating Scale, Revised (ALSFRS-R) scorewhen compared to baseline. In particular embodiments, the subjectexhibits a greater than 30% improvement in ALS Functional Rating Scale,Revised (ALSFRS-R) score when compared to baseline. The ALSFRS-Rmeasures 4 domains: pulmonary function, bulbar function, and gross andfine motor skills. There are a total of 12 questions, each scored from 0to 4 for a total possible score of 48. The twelve questions and ratingscale are provided in Cederbaum, et al., 169 J. NEUROL. SCI., 13-21(1999) which is incorporated herein in its entirety.

In some embodiments, treating ALS can include slowing progression ofALS, reducing intensity of symptoms associated with ALS, reducing onsetof symptoms associated with ALS, reducing weight loss associated withALS, reversing weight loss associated with ALS, delaying mortality, andcombinations thereof. In particular embodiments, the symptoms associatedwith ALS may be, for example, decreases in fine motor function,decreases in gross motor function, decreases in bulbar function,decreases in respiratory function, and combinations thereof. Further, inother embodiments, the symptoms associated with ALS can includedifficulty with daily activities, such as, for example, difficulty withwalking, speech, eating, swallowing, writing, climbing stairs, cuttingfood, turning in bed, dressing, maintaining hygiene, and combinationsthereof, and may experience other symptoms, such as, for example,difficulty breathing, dyspnea, orthopnea, respiratory insufficiency,increased salivation and combinations thereof. In particular embodimentsof the various methods, a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, may be usedto treat ALS. For example, in some embodiments, individuals diagnosedwith ALS within two years or less may be treated with a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, to reduce, eliminate, or slow advancement ofALS or symptoms associated with ALS such as, for example, fine motorfunction loss, gross motor function loss, loss of bulbar function, andloss of respiratory function. In other embodiments, a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, may be administered to reduce or slow theadvancement of symptoms including, but not limited to, trembling, lossof muscle control, loss of ability to write, loss of ability to move orroll over, loss of speech, inability to swallow, difficulty breathing,and so on. In other embodiments, individuals with advanced symptoms orindividuals who were diagnosed with ALS more than two years beforebeginning treatment may be treated with a compound of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, and such individuals may respond to treatment by exhibiting areduction or elimination of one or more symptoms related to ALS, or incertain embodiments, the rate of symptom onset or advancement may bereduced, for example; the rate of motor function loss, the rate of lossof speech, and/or difficulty swallowing may be slowed and/or reduced.

In embodiments, the subject is administered a therapeutically effectiveamount of a compound of formula A-1 through A-44 or B-1 through B-7, ora pharmaceutically acceptable salt thereof, and the decline of muscleloss is reduced. In embodiments, the subject is administered atherapeutically effective amount of a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,and the decline of serum creatinine is reduced. In additionalembodiments of the various methods, compound of formula A-1 through A-44or B-1 through B-7, or a pharmaceutically acceptable salt thereof, maybe administered to subjects in need of treatment for excessive weightloss associated with ALS. Without wishing to be bound by theory, theprecipitous weight loss that is a cardinal symptom of ALS may beassociated with increased energy expenditure, skeletal musclehypermetabolism, and the systematic wasting of muscle tissue known ascachexia.

In some embodiments, the method is carried out for a time periodselected from at least about twelve months, at least about eighteenmonths, at least about two years, at least about four years, at leastabout six years, at least about eight years, at least about ten years,at least about twenty years, and until the subject dies. In otherembodiments, the method is carried out at least daily for an indefiniteamount of time.

The present application provides for a method of identifying a patientwho will respond to treatment with a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,comprising: diagnosing a patient with EEC definite ALS; measuring theserum creatinine levels of the patient; and identifying the patient as aresponder if the serum creatinine levels are greater than about 72μmol/L. Some embodiments include methods of identifying a subject thatwill likely respond to treatments described herein. In some embodiments,the subject will exhibit one or more of the following characteristics:definite ALS as defined by the El Escorial diagnosis criteria,amyotrophic lateral sclerosis symptom onset duration of less than about18 months, limb-onset amyotrophic lateral sclerosis, plasma creatininelevels of about 72 μM/L or greater, concomitant riluzole administration,concomitant dexpramipexole administration, an ALSFRS-R score of greaterthan 36.0, a re-study progression rate greater than or equal to 0.8points per month, a percentage predicted relaxed (slow) vital capacity(SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domainscore of greater than 10.0 points, ALSFRS-R bulbar domain score orgreater than 9.0 points, an ALSFRS-R gross motor domain score of greaterthan 8.0 points, an abnormal neurological exam of the tongue, anabnormal neurological exam of the pharynx, larynx and swallowing, anabnormal neurological exam of the lower extremities, an abnormalneurological exam of the upper extremities, an abnormal neurologicalexam of the triceps, an abnormal neurological exam of the muscle massand bulk, an abnormal neurological exam of the bicep, an abnormalneurological exam, a pulse rate of greater than 81.0 beats per minute, adiastolic blood pressure of greater than 82.0 mmHg, a systolic bloodpressure of less than or equal to 117.0 mmHg, a creatinine value ofgreater than 72.0 μmol/L, a phosphorous value of less than or equal to1.090 μmol/L, a platelet count of less than or equal to 248.0×10⁹cells/L, a cholesterol value of less than or equal to 5.3 mmol/L, alactate dehydrogenase value of less than or equal to 161.0 U/L, acreatine phosphokinase value of less than or equal to 184.0 U/L, abicarbonate value of less than or equal to 21.6 mmol/L, a triglyceridelevel of less than or equal to 1.4 mmol/L, a uric acid level of greaterthan 320.0 μmol/L, a gamma-glutamyltransferase (GGT)level of greaterthan 37.0 U/L, a total bilirubin level of less than or equal to 6.0μmol/L, a urine pH of less than or equal to 5.5, or any combinationthereof. In some embodiments, the subject will have at least one of theabove characteristics. In some embodiments, the subject will have morethan one of the above characteristics. In embodiments, the methodfurther comprises monitoring said subject for any clinical featuresassociated with amyotrophic lateral sclerosis. In embodiments, themethod further comprises initiating therapy with a therapeuticallyeffective amount of(6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole or apharmaceutically acceptable salt thereof upon diagnosis of amyotrophiclateral sclerosis. In certain embodiments, the subject exhibits symptomsof amyotrophic lateral sclerosis. In certain embodiments, the subjecthas definite amyotrophic lateral sclerosis, probable amyotrophic lateralsclerosis, possible amyotrophic lateral sclerosis or suspectedamyotrophic lateral sclerosis.

The structures associated with some of the chemical names referred toherein are depicted below. These structures may be unsubstituted, asshown below, or a substituent may independently be in any positionnormally occupied by a hydrogen atom when the structure isunsubstituted. Unless a point of attachment is indicated by

attachment may occur at any position normally occupied by a hydrogenatom.

Formulas A and B

Some embodiments include a compound represented by Formula A-1:

With respect to Formula A-1 or any embodiments of Formula A-1, A isoptionally substituted imidazo[4,5-b]pyridin-2-yl, such as optionallysubstituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted3H-imidazo[4,5-b]pyridin-2-yl. If the imidazo[4,5-b]pyridin-2-yl issubstituted, it may have 1, 2, 3, or 4 substituents. Any substituent maybe included on the imidazo[4,5-b]pyridin-2-yl. In some embodiments, someor all of the substituents on the imidazo[4,5-b]pyridin-2-yl may have:from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein eachheteroatom is independently: O, N, S, F, Cl, Br, or I (provided thatthere is at least 1 non-hydrogen atom); and/or a molecular weight of 15g/mol to 500 g/mol. For example, the substituents may be C₁₋₁₀optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅,C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., whichmay be optionally substituted; C₁₋₁₀ optionally substituted alkoxy suchas OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclicOC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I; OH; CN;NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy,such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as —O₂CCH₃,—CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc.

In some embodiments, any or all of the substituents of1H-imidazo[4,5-b]pyridin-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl areindependently CF₃, Cl, CN, or OCH₃. In some embodiments, A has a CF₃substituent. In some embodiments, A has a Cl substituent. In someembodiments, A has a CN substituent. In some embodiments, A has an OCH₃substituent.

In some embodiments of Formula A-1, A may be:

Some embodiments of Formula A-1 may include a compound represented byone or more of Formulas A-2 through A-42 or a pharmaceuticallyacceptable salt thereof:

With respect to any relevant embodiment or structural representation ofFormula A-1 herein, such as Formulas A-1 through A-42, L is CH₂, CF₂,C₂H₄ (such as CH₂CH₂, CH(CH₃), etc.), C₃H₆ (such as CH₂CH₂CH₂,CH₂CH(CH₃), CH(CH₃)CH₂, CH(CH₃)₂, etc.), O, CH₂O, C₂H₄O (such as OCH₂CH₂(where the O atom may be on either side of the CH₂CH₂), CH₂OCH₂,OCH(CH₃), etc.), or C₃H₆O.

In some embodiments of Formula A-1, such as Formulas A-1 through A-42, Lis CH₂, CF₂, CH₂CH₂, CH(CH₃)₂, or CH(CH₃).

In some embodiments of Formula A-1, such as Formulas A-1 through A-42, Lis CH₂.

In some embodiments of Formula A-1, such as Formulas A-1 through A-42, Lis CH₂CH₂.

In some embodiments of Formula A-1, such as Formulas A-1 through A-42, Lis CH(CH₃)₂.

In some embodiments of Formula A-1, such as Formulas A-1 through A-42, Lis CH(CH₃).

With respect to any relevant embodiment or structural representation ofFormula A-1 herein, such as Formulas A-1 through A-42, R¹ may be C₁₋₁₂optionally substituted alkyl, such as optionally substituted CH₃,optionally substituted C₂H₅, optionally substituted C₃H₇, optionallysubstituted cyclic C₃H₅, optionally substituted C₄H₉, optionallysubstituted cyclic C₄H₇, optionally substituted C₅H₁₁, optionallysubstituted cyclic C₅H₉, optionally substituted C₆H₁₃, optionallysubstituted cyclic C₆H₁₁, optionally substitutedbicyclo[2.2.1]heptan-2-yl, optionally substitutedbicyclo[3.1.1]heptan-2-yl, etc.; C₁₋₁₂ optionally substituted —O-alkyl,such as optionally substituted —O—CH₃, optionally substituted —O—C₂H₅,optionally substituted —O—C₃H₇, optionally substituted cyclic —O—C₃H₅,optionally substituted —O—C₄H₉, optionally substituted cyclic —O—C₄H₇,optionally substituted —O—C₅H₁₁, optionally substituted cyclic —O—C₅H₉,optionally substituted —O—C₆H₁₃, optionally substituted cyclic —O—C₆H₁₁,optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy, etc.; optionallysubstituted C₆₋₁₀ aryl, such as optionally substituted phenyl;optionally substituted C₆₋₁₀—O-aryl, such as optionally substituted—O-phenyl; or optionally substituted C₂₋₉ heterocyclyl, such asoptionally substituted isoxazolyl, optionally substitutedtetrahydropyranyl, optionally substituted tetrahydrofuranyl, etc. Insome embodiments, R¹ is CH₃, C₂₋₁₂ optionally substituted alkyl, C₁₋₁₂optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉heterocyclyl.

With respect to any relevant embodiment or structural representation ofFormula A-1 herein, such as Formulas A-1 through A-42, in someembodiments, R¹ is optionally substituted phenyl. In some embodiments,R¹ is C₃₋₄ alkyl. In some embodiments, R¹ is optionally substitutedbicyclo[2.2.1]heptan-2-yl. In some embodiments, R¹ is optionallysubstituted isoxazol-3-yl. In some embodiments, R¹ is CF₃. In someembodiments, R¹ is optionally substituted cyclopentyl. In someembodiments, R¹ is optionally substituted cyclohexyl. In someembodiments, R¹ is methyl. In some embodiments, R¹ is optionallysubstituted bicyclo[3.1.1]heptan-2-yl. In some embodiments, R¹ isoptionally substituted —O— phenyl. In some embodiments, R¹ is optionallysubstituted CH(CF₃)₂. In some embodiments, R¹ is C₂₋₄—O-alkyl. In someembodiments, R¹ is optionally substituted adamantan-1-yl. In someembodiments, R¹ is optionally substituted tetrahydro-2H-pyranyl. In someembodiments, R¹ is optionally substituted(2,3-dihydro-1H-inden-1-yl)oxy. In some embodiments, R¹ is optionallysubstituted tetrahydrofuranyl.

With respect to any relevant embodiment or structural representation ofFormula A-1 herein, such as Formulas A-1 through A-42, in someembodiments, R¹ can be one of the following:

With respect to any relevant embodiment or structural representation ofFormula A-1 herein, such as Formulas A-2 and A-42 through A-42, R² is—R^(α)-Cy. R^(α) is a bond or C₁₋₁₂ optionally substituted alkyl, suchas CH₂, C₂H₄, C₃H₆, C₄H₈, C₅H₁₀, C₆H₁₂, cyclic C₃H₅, cyclic C₄H₇, cyclicC₅H₉, cyclic C₆H₁₁, etc. Cy is H; optionally substituted C₆₋₁₀ aryl,such as optionally substituted phenyl; or optionally substituted C₂₋₉heterocyclyl, such as optionally substituted azetidinyl, optionallysubstituted oxatanyl, optionally substituted thietanyl, etc. In someembodiments, R² is optionally substituted cyclobutyl or optionallysubstituted 2-methylpropyl. In some embodiments, R² is:

In some embodiments of Formula A-1 through A-44, R² is cyclobutyl. Insome embodiments, R² is 2-methylpropyl.

To any relevant embodiment or structural representation of Formula A-1through A-44 herein the following applies. Generally R³-R⁵², may be H orany substituent, such as a substituent having 0 to 12 atoms or 0 to 6carbon atoms and 0 to 5 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I, and/or having a molecularweight of 15 g/mol to 300 g/mol. Any of R³-R⁵² may comprise: a) 1 ormore alkyl moieties optionally substituted with, or optionally connectedby or to, b) 1 or more functional groups, such as C═C, C≡C, CO, CO₂,CON, NCO₂, OH, SH, O, S, N, N═C, F, Cl, Br, I, CN, NO₂, CO₂H, NH₂, etc.;or may be a substituent having no alkyl portion, such as F, Cl, Br, I,NO₂, CN, NH₂, OH, COH, CO₂H, etc.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl),cyclopropyl, butyl isomers, cyclobutyl isomers (e.g. cyclobutyl andmethylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers,cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl,isomers of —O-propyl, —O— cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³ maybe H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂optionally substituted —O-alkyl, optionally substituted C₂₋₉heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂optionally substituted acylamino, C₁₋₁₂ optionally substitutedaminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl (or alkyl with anamino substituent). In some embodiments, R³ may be H, CH₃, OH, OCH₃,NH₂, NHCH₃, N(CH₃)₂, COH, COCH₃, CF₃, Cl, CN, or OCH₃. In someembodiments, R³ may be H, CF₃, Cl, CN, or OCH₃. In some embodiments, R³is H. In some embodiments, R³ is CF₃. In some embodiments, R³ is Cl. Insome embodiments, R³ is CN. In some embodiments, R³ is OCH₃.

To any relevant embodiment or structural representation of Formula A-1through A-44 herein the following applies. Each R^(A) may independentlybe H, or C₁₋₁₂ alkyl, including: linear or branched alkyl having aformula C_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a−1),wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear orbranched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅,C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇,C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments,R^(A) may be H or C₁₋₆ alkyl. In some embodiments, R^(A) may be H orC₁₋₃ alkyl. In some embodiments, R^(A) may be H or CH₃. In someembodiments, R^(A) may be H.

To any relevant embodiment or structural representation of Formula A-1through A-44 herein the following applies. Each R^(B) may independentlybe H, or C₁₋₁₂ alkyl, including: linear or branched alkyl having aformula C_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a), whereina is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear orbranched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₈H₁₇,C₇H₁₅, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇,C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments,R^(B) may be H or C₁₋₃ alkyl. In some embodiments, R^(B) may be H orCH₃. In some embodiments, R^(B) may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc., or —O—C₁₋₆ alkyl, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴ maybe H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂optionally substituted —O-alkyl, optionally substituted C₂₋₉heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂optionally substituted acylamino, C₁₋₁₂ optionally substitutedaminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl. In someembodiments, R⁴ may be H, CF₃, or C₁. In some embodiments, R⁴ is H. Insome embodiments, R⁴ is CF₃. In some embodiments, R⁴ is Cl.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁵ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵ maybe H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂optionally substituted —O-alkyl, optionally substituted C₂₋₉heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂optionally substituted acylamino, C₁₋₁₂ optionally substitutedaminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl. In someembodiments, R⁵ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. Insome embodiments, R⁵ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁶ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁶ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁶ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁷ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁷ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁷ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁸ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁸ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁸ is H. Insome embodiments, R⁸ is F.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁹ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁰ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁰ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R¹⁰ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹¹ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹¹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹² mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹² isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹² may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹³ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹³ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹³ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁴ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁴ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁴ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹¹ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁵ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁶ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁶ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁶ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁷ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁷ isH, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁷ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁸ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁸ maybe H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In someembodiments, R¹⁸ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹⁹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁹ maybe H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments,R¹⁹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁰ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁰ maybe H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In someembodiments, R²⁰ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²¹ maybe H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments,R²¹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²² mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²² maybe H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In someembodiments, R²² may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²³ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²³ maybe H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments,R²³ is H. In some embodiments, R²³ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁴ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁴ maybe H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In someembodiments, R²⁴ is H. In some embodiments, R²⁴ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁵ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁵ maybe H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments,R²⁵ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁶ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁶ maybe H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁶ may beH.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁷ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁷ maybe H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁷ may beH.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁸ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁸ maybe H, F, CN, CF₃, or CH₃. In some embodiments, R²⁸ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R²⁹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R²⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁹ maybe H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁹ may beH.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁰ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁰ maybe H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In someembodiments, R³⁰ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³¹ maybe H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments,R³¹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³² mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³² maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R³² may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³³ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³³ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R³³ is H. In someembodiments, R³³ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁴ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁴ maybe H, F, Cl, OH, CN, CF₃, CH₃, NH₂, NHCH₃, N(CH₃)₂, or —OCH₃. In someembodiments, R³⁴ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁵ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁵ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R³⁵ is H. In some embodiments, R³⁵ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁶ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁶ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R³⁶ is H. In some embodiments, R³⁶ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁷ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁷ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R³⁷ is H. In some embodiments, R³⁷ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁸ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁸ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R³⁸ is H. In some embodiments, R³⁸ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R³⁹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R³⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁹ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R³⁹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁰ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R⁴⁰ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴¹ maybe H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In someembodiments, R⁴¹ is H. In some embodiments, R⁴¹ is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴² mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴² maybe H, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments,R⁴² is H. In some embodiments, R⁴² is CH₃.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴³ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴³ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴³ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁴ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁴ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁴ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁵ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁵ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁵ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁶ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁶ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁶ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁷ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁷ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁷ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁸ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁸ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁸ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁴⁹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁴⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁹ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁵⁰ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁵⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵⁰ maybe H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵⁰ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R¹ mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹ maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵¹ may be H.

With respect to any relevant embodiment or structural representation ofFormula A-1 through A-44 herein, some non-limiting examples of R⁵² mayinclude R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, R⁵² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutylisomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexylisomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of—O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵² maybe H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵² may be H.

Some embodiments of Formula A-1 may include a compound represented byFormula A-43:

-   -   wherein        -   L is CH₂;        -   R¹ is optionally substituted cyclic C₃H₅, wherein the            optional substituent of R¹ is CF₃;        -   R² is optionally substituted cyclobutyl;        -   R³ is optionally substituted C₃ alkyl, wherein the optional            substituents of R³ is OH;        -   R⁴ is H; and        -   R⁵ is H;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula A-1 may include a compound represented byFormula A-44:

-   -   wherein        -   L is CH₂;        -   R¹ is optionally substituted C₂ alkyl, wherein the optional            substituents of R¹ are independently CF₃ or CH₃;        -   R² is optionally substituted cyclobutyl;        -   R³ is optionally substituted C₃ alkyl, wherein the optional            substituents of R³ is OH;        -   R⁴ is H; and        -   R⁵ is H;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula A-1 include a compound represented by thefollowing structures or a pharmaceutically acceptable salt thereof:

Some embodiments include a compound represented by Formula B-1:

With respect to Formula B-1, or any embodiments of Formula B-1, Bz canbe optionally substituted benzoimidazol-1,2-yl. If thebenzoimidazol-1,2-yl is substituted, it may have 1, 2, 3, or 4substituents. Any substituent may be included on thebenzoimidazol-1,2-yl. In some embodiments, some or all of thesubstituents on the benzoimidazol-1,2-yl may have: from 0 to 10 carbonatoms and from 0 to 10 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I (provided that there is at least1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500g/mol. In some embodiments, some or all of the substituents may eachhave a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to50 Da, and consist of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br. In someembodiments, Bz can be optionally substituted benzoimidazol-1,2-diyl. Insome embodiments, Bz can be optionally substitutedbenzoimidazol-1,2,6-triyl.

For example, with respect to Formula B-1, or any embodiments of FormulaB-1, the substituents of Bz may be C₁₋₁₀ optionally substituted alkyl,such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclicC₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., which may be optionally substituted;C₁₋₁₀ optionally substituted alkoxy such as OCH₃, OC₂H₅, OC₃H₇, cyclicOC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁,etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl, such asCF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅,etc.; a C₁₋₁₀ ester such as —O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅,—O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone such as —COCH₃, —COC₂H₅,—COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such as NH₂, NH(CH₃),N(CH₃)₂, N(CH₃)C₂H₅, etc. In some embodiments, a substituent of Bz maybe F, Cl, Br, I, CN, NO₂, C₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃,COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄ CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

Some embodiments of Formula B-1 may include a compound represented byFormulas B-2:

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, D is optionallysubstituted C₃₋₆ carbocyclyl or C₂₋₅ heterocyclyl. If D is substitutedcyclobutyl, it may have 1, 2, 3, 4, 5, 6, or 7 substituents. If D issubstituted phenyl, it may have 1, 2, 3, 4, or 5 substituents. If D issubstituted isoxazolyl, it may have 1 or 2. D may include anysubstituent. In some embodiments, some or all of the substituents of Dmay have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms,wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I(provided that there is at least 1 non-hydrogen atom); and/or amolecular weight of 15 g/mol to 500 g/mol. In some embodiments, some orall of the substituents may each have a molecular weight of 15 Da to 200Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,F, Cl, or Br.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, the substituentsof D may be C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇,cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁,etc., which may be optionally substituted; C₁₋₁₀ optionally substitutedalkoxy such as OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇,OC₅H₁₁, cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl,Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.;C₁₋₆ fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester suchas —O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.;a C₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or aC₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of D may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is:

optionally substituted C₂₋₄ alkyl.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is optionally substituted cyclobutyl, optionallysubstituted phenyl, optionally substituted isoxazolyl, or isopropyl.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is optionally substituted cyclobutyl. In someembodiments, D is cyclobutyl. In some embodiments, D is

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is isopropyl.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is t-butyl, or tert-butyl.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is optionally substituted phenyl. In some embodiments, Dis

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is optionally substituted pyridinyl, such as optionallysubstituted pyridinyl-2-yl, pyridin-3-yl, or pyridin-4-yl. In someembodiments, D is

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments, D is optionally substituted isoxazolyl. In someembodiments, D is

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, A is C₂₋₈ alkyl,such as linear or branched

linear or branched

linear or branched

linear or branched

linear or branched

containing one ring,

containing one ring,

containing one ring,

containing one ring, or

containing a bicyclic ring system.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, X is H, F, CF₃,optionally substituted phenyl, or optionally substituted pyridinyl. Insome embodiments, X is H. In some embodiments, X is F. In someembodiments, X is CF₃.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, if X issubstituted phenyl, it may have 1, 2, 3, 4, or 5, substituents. If X issubstituted pyridinyl, it may have 1, 2, 3, or 4 substituents. In someembodiments, some or all of the substituents of X may have: from 0 to 10carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I (provided that there is at least1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500g/mol. In some embodiments, some or all of the substituents may eachhave a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to50 Da, and consist of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, the substituentsof X may be C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇,cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁,etc., which may be optionally substituted; C₁₋₁₀ optionally substitutedalkoxy such as OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇,OC₅H₁₁, cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl,Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.;C₁₋₆ fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester suchas —O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.;a C₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or aC₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of X may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, Y is H, F, Cl,Br, I, or a moiety having a molecular weight of 15 Da to 300 Da andconsisting of 2 to 5 chemical elements, wherein the chemical elementsare independently C, H, O, N, S, F, Cl, or Br. In some embodiments, Y isH, F, Cl, Br, I, CN, —COH, C₁₋₆—CO-alkyl, CF₃, OH, C₁₋₅ O-alkyl, C₃₋₆amino, or C₃₋₆ fluoroamino. In some embodiments, Y is H, F, CF₃, OH,C₁₋₅ O-alkyl, C₃₋₆ amino, or C₃₋₆ fluoroamino. In some embodiments, Y isH. In some embodiments, Y is OH. In some embodiments, Y is F. In someembodiments, Y is CF₃. In some embodiments, Y is C₁₋₃ O-alkyl, such as—OCH₃, OC₂H₅, OC₃H₇, etc. In some embodiments, Y is C₀₋₆ fluoroamino. Insome embodiments, Y is optionally substituted tetrahydropyranyl, such as

In some embodiments Y may include a C₁₋₅ alkyl that may include one ortwo C₃₋₆ carbocyclyl rings. In some embodiments, wherein Y includes atleast one carbocyclyl rings, the rings may be connected to each other.In some embodiments, Y is —C(CF₃)₂OH (or1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments Y is

(or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y isdimethylamino.

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is C₂₋₈ alkyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is C₂₋₈ hydroxyalkyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is C₂₋₈ fluoroalkyl such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is C₂₋₈ alkoxyalkyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is C₂₋₈ hydroxyfluoroalkyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is optionally substituted 2-hydroxy-2-phenylethyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is optionally substituted 2-hydroxy-2-phenylpyridinyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies, in someembodiments

is optionally substituted C₂₋₈ fluoroaminoalkyl, such as

To any relevant embodiment or structural representation of Formula B-1or B-2 or B-3 through B-7 herein the following applies. Generally R¹⁻¹⁸,may be H or any substituent, such as a substituent having 0 to 12 atomsor 0 to 6 carbon atoms and 0 to 5 heteroatoms, wherein each heteroatomis independently: O, N, S, F, Cl, Br, or I, and/or having a molecularweight of 15 g/mol to 300 g/mol. Any of R¹⁻¹⁸ may comprise: a) 1 or morealkyl moieties optionally substituted with, or optionally connected byor to, b) 1 or more functional groups, such as C═C, C≡C, CO, CO₂, CON,NCO₂, OH, SH, O, S, N, N═C, F, Cl, Br, I, CN, NO₂, CO₂H, NH₂, etc.; ormay be a substituent having no alkyl portion, such as F, Cl, Br, I, NO₂,CN, NH₂, OH, COH, CO₂H, etc. In some embodiments, each of R¹⁻¹⁸ isindependently H, F, Cl, Br, I, or a substituent having a molecularweight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to60 Da, and consisting of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, some non-limiting examples of R¹⁻¹⁸ may includeR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, R¹⁻¹⁸ may be H; F; Cl; Br; CN; C₁₋₃fluoroalkyl, such as CHF₂, CF₃, etc; OH; NH₂; C₁₋₆ alkyl, such asmethyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl),cyclopropyl, butyl isomers, cyclobutyl isomers (e.g. cyclobutyl andmethylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers,cyclohexyl isomers, etc.; C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl,isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of—O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomersof —O-hexyl, isomers of —O-cyclohexyl, etc.; C₁₋₄ hydroxyalkyl, such as—CH₂OH, —C₂H₄—OH, —C₃H₆—OH, C₄H₈—OH, etc.; C₂₋₅—CO₂-alkyl, such as—CO₂—CH₃, —CO₂—C₂H₅, —CO₂—C₃H₇, —CO₂—C₄H₉, etc.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, each R^(A) may independently be H, or C₁₋₁₂alkyl, including: linear or branched alkyl having a formulaC_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a−1), wherein a is1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branchedalkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇,C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇, C₅H₉,C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^(A) maybe H or C₁₋₆ alkyl. In some embodiments, R^(A) may be H or C₁₋₃ alkyl.In some embodiments, R^(A) may be H or CH₃. In some embodiments, R^(A)may be H.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, each R^(B) may independently be H, or C₁₋₁₂alkyl, including: linear or branched alkyl having a formulaC_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a−1), wherein a is1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branchedalkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇,C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇, C₅H₉,C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^(B) maybe H or C₁₋₃ alkyl. In some embodiments, R^(B) may be H or CH₃. In someembodiments, R^(B) may be H.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, such as Formula B-2, in some embodiments R¹ isH, F, Cl, Br, CN, OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄hydroxyalkyl. In some embodiments, R¹ is H, Cl, Br, CN, OCH₃, CHF₂, CF₃,—CO₂CH₂CH₃, —CH₂OH,

In some embodiments, R¹ is H. In some embodiments, R¹ is Cl. In someembodiments, R¹ is Br. In some embodiments, R¹ is CN. In someembodiments, R¹ is OCH₃. In some embodiments, R¹ is CHF₂. In someembodiments, R¹ is CF₃. In some embodiments, R¹ is —CO₂CH₂CH₃. In someembodiments, R¹ is —CH₂OH. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is —OCH₃, —CN, —CF₃, —CH₂OH, —COOCH₂CH₃,—C(CH₃)₂OH, —CHOHCH₂CH₃, —CHOHCH₃, —CHF₂, —CH(CH₃)₂, —C(CH₂CH₃)OH,—CH₂COOC H₂CH₃, —CH₂C(CH₃)₂OH, —CH₂COOH, or —CH₂CON(CH₃)₂. With respectto the embodiments recited in this paragraph, in some embodiments, theremaining groups of R¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN,OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₅hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R² is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R² is H. In some embodiments, R² is CH₂OH. In someembodiments, R² is —CO₂CH₃. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl. In someembodiments, R² is —CH₂OH, —CO₂Me, or —C(CH₃)₂OH.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R³ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R³ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁴ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁴ is H. In some embodiments, R⁴ is CH₃. In someembodiments, R⁴ is CF₃. With respect to the embodiments recited in thisparagraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁵ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁵ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁶ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁶ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁷ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁷ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁸ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁸ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R⁹ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R⁹ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R¹⁰ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R¹⁰ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R¹¹ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R¹¹ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R¹² is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R¹² is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R¹³ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R¹³ is H. With respect to the embodiments recited inthis paragraph, in some embodiments, the remaining groups of R¹⁻¹⁸ mayindependently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A),NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, the remaininggroups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation of Formula B-1 orB-2 or B-3 through B-7, in some embodiments R¹⁴ is H, F, Cl, Br, CN,OCH₃, CHF₂, CF₃, C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. Insome embodiments, R¹⁴ is H. In some embodiments, R¹⁴ is F. With respectto the embodiments recited in this paragraph, in some embodiments, theremaining groups of R¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN,OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), etc. In someembodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄hydroxyalkyl.

In some embodiments of the invention, one or more hydrogen atoms isreplaced by a deuterium. It is well established that deuteration ofphysiologically active compounds offer the advantage of retaining thepharmacological profile of their hydrogen counterparts while positivelyimpacting their metabolic outcome. Selective replacement of one or morehydrogen with deuterium, in a compound of the present invention, couldimprove the safety, tolerability and efficacy of the compound whencompared to its all hydrogen counterpart.

Methods for incorporation of deuterium into compounds is wellestablished. Using metabolic studies establish in the art, the compoundof the present invention can be tested to identify sites for selectiveplacement of a deuterium isotope, wherein the isotope will not bemetabolized. Moreover these studies identify sites of metabolism as thelocation where a deuterium atom would be placed.

Some embodiments of Formula B-1 may include a compound represented byFormula B-3:

-   -   wherein        -   D is optionally substituted cyclobutyl;        -   A is C₄ alkyl;        -   X is CF₃;        -   Y is H;        -   R¹ is C₃ hydroxyalkyl;        -   R² and R⁴ are H; and        -   R³ is F;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula B-1 may include a compound represented byFormula B-4:

-   -   wherein        -   D is optionally substituted cyclobutyl;        -   A is C₄ alkyl;        -   X is CF₃;        -   Y is H;        -   R¹ is C₃ hydroxyalkyl; and        -   R², R³ and R⁴ are H;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula B-1 may include a compound represented byFormula B-5:

-   -   wherein        -   D is t-butyl;        -   A is C₅ alkyl;        -   X is H;        -   Y is H;        -   R¹ is CN;        -   R² and R⁴ are H; and        -   R³ is F;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula B-1 may include a compound represented byFormula B-6:

-   -   wherein        -   D is t-butyl;        -   A is C₄ alkyl;        -   X is CF₃;        -   Y is H;        -   R¹ is CN;        -   R² and R⁴ are H; and        -   R³ is F;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula B-1 may include a compound represented byFormula B-7:

-   -   wherein        -   D is t-butyl;        -   A is C₅ alkyl;        -   X is H;        -   Y is H;        -   R¹ is CN;        -   R² and R³ are F; and        -   R⁴ is H;        -   or a pharmaceutically acceptable salt thereof.

Some embodiments of Formula B-1 include a compound represented by thefollowing structures or a pharmaceutically acceptable salt thereof:

Compounds disclosed herein may be synthesized by the methods disclosedin U.S. Pat. Nos. 9,650,376 and 9,481,653, which are incorporated byreference herein.

In embodiments described herein, the therapeutically effective amount ofa compound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof, may be from about 0.1 mg/dayto about 3,000 mg/day. In such embodiments of the various methods, thepharmaceutical composition suitable for oral administration may includeat least about 50 milligrams of a compound of formula A-1 through A-44or B-1 through B-7, or a pharmaceutically acceptable salt thereof, andin some embodiments, such pharmaceutical compositions may include atleast about 75 milligrams of a compound of formula A-1 through A-44 orB-1, at least about 100 milligrams of a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,at least about 150 milligrams of a compound of formula A-1 through A-44or B-1 through B-7, or a pharmaceutically acceptable salt thereof, atleast about 200 milligrams of a compound of formula A-1 through A-44 orB-1 through B-7, or a pharmaceutically acceptable salt thereof, at leastabout 250 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, at leastabout 300 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, at leastabout 500 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, at leastabout 600 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, at leastabout 750 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, or at leastabout 1000 milligrams of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of formula A-1 through A-44 or B-1 throughB-7, or a pharmaceutically acceptable salt thereof, may be administeredin a pharmaceutical composition. The pharmaceutical compositions of thevarious methods may be prepared, packaged, sold in bulk, as a singleunit dose, or as multiple unit doses, and can be administered in theconventional manner by any route where they are active. For example, thecompositions may be administered orally, ophthalmically, intravenously,intramuscularly, intra-arterially, intramedullary, intrathecally,intraventricularly, transdermally, subcutaneously, intraperitoneally,intravesicularlly, intranasally, enterally, topically, sublingually,rectally by inhalation, by depot injections, or by implants or by use ofvaginal creams, suppositories, pessaries, vaginal rings, rectalsuppositories, intrauterine devices, and transdermal forms such aspatches and creams. Specific modes of administration will depend on theindication. The selection of the specific route of administration andthe dose regimen may be adjusted or titrated by the clinician accordingto known methods in order to obtain the optimal clinical response. Allof the methods described herein may be carried out by administering acompound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof, by any such route foradministration described herein. Additionally, a compound of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, may be delivered by using any such route of administration forthe entire dosage regimen described herein.

Pharmaceutical compositions containing a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,in a solid dosage may include, but are not limited to, tablets,capsules, cachets, pellets, pills, powders, and granules; topical dosageforms which include, but are not limited to, solutions, powders, fluidemulsions, fluid suspensions, semi-solids, ointments, pastes, creams,gels and jellies, and foams; and parenteral dosage forms which include,but are not limited to, solutions, suspensions, emulsions, and drypowder; comprising an effective amount of a polymer or copolymer. It isalso known in the art that the active ingredients can be contained insuch formulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

For oral administration, a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, can beformulated readily by combining these a compound of formula A-1 throughA-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof,with pharmaceutically acceptable carriers well known in the art. Suchcarriers enable the compounds of the various methods to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a subject to be treated.Pharmaceutical preparations for oral use can be obtained by adding asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations including, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

In some embodiments of the various methods, pharmaceutical compositionsmay be suitable for oral administration such as, for example, a solidoral dosage form or a capsule, and in certain embodiments, thecomposition may be a tablet. Such tablets may include any number ofadditional agents such as, for example, one or more binder, one or morelubricant, one or more diluent, one or more lubricant, one or moresurface active agent, one or more dispersing agent, one or morecolorant, and the like. Such tablets may be prepared by any method knownin the art, for example, by compression or molding. Compressed tabletsmay be prepared by compressing in a suitable machine the ingredients ofthe composition in a free-flowing form such as a powder or granules, andmolded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent. Thetablets, of some embodiments, may be uncoated and, in other embodiments,they may be coated by known techniques.

In other embodiments of the various methods prepared for oraladministration, the pharmaceutical compositions of the various methodsmay be provided in a dragee cores with suitable coatings. In suchembodiments, dragee cores may be prepared suing concentrated sugarsolutions, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide,lacquer solutions, and suitable organic solvents or solvent mixtures. Insome embodiments, dyestuffs or pigments may be added to the tablets ordragee coatings for identification or to characterize differentcombinations of active compound doses. In yet other embodiments,pharmaceutical compositions including an effective amount of a compoundof formula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, prepared for oral administration may include,but are not limited to, push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. The push-fit capsules can contain the activeingredients in admixture with filler such as, for example, lactose,binders such as, for example, starches, and/or lubricants such as, forexample, talc or magnesium stearate and, optionally, stabilizers. Insoft capsules, the active compounds can be dissolved or suspended insuitable liquids, such as fatty oils, liquid paraffin, or liquidpolyethylene glycols. In addition, stabilizers can be added. Allformulations for oral administration should be in dosages suitable forsuch administration.

In embodiments of the various methods in which the tablets and drageecores are coated, the coatings may delay disintegration and absorptionin the gastrointestinal tract and thereby provide a sustained actionover a longer period. Additionally, such coatings may be adapted forreleasing a compound of formula A-1 through A-44 or B-1 through B-7, ora pharmaceutically acceptable salt thereof, in a predetermined pattern,for example, in order to achieve a controlled release formulation, or itmay be adapted to not release the active compound until after passage ofthe stomach by including, for example, an enteric coating. Suitablecoatings encompassed by such embodiments may include, but are notlimited to, sugar coating, film coating, such as, for example,hydroxypropyl methylcellulose, methyl-cellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,acrylate copolymers, polyethylene glycols, and/or polyvinylpyrrolidone,or an enteric coating, such as, for example, methacrylic acid copolymer,cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, shellac, and/or ethylcellulose. Furthermore, a time delaymaterial such as, for example, glyceryl monostearate or glyceryldistearate may be incorporated into the coatings of some embodiments. Instill other embodiments, solid tablet compositions may include a coatingadapted to protect the composition from unwanted chemical changes, forexample, to reduce chemical degradation prior to the release of theactive drug substance.

Pharmaceutical compositions suitable for oral administration encompassedin embodiments of the various methods may include a therapeuticallyeffective amount of a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, and mayfurther include one or more diluents, one or more disintegrants, one ormore lubricants, one or more pigments or colorants, one or moregelatins, one or more plasticizers, and the like. For example, in someembodiments, a tablet may include an effective amount of a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, from about 20% to about 50% by weight ofdiluent in an amount, from about 10% to about 30% by weight of a seconddiluent, from about 2% to about 6% by weight of a disintegrant, and fromabout 0.01% to about 2% by weight of a lubricant, and in particularembodiments, such tablets may include an effective amount of a compoundof formula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, from about 20% to about 50% by weightmicrocrystalline cellulose, about 10% to about 30% by weight mannitol,from about 2% to about 6% crospovidone or croscarmellose, and from about0.01% to about 2% by weight magnesium stearate. In further embodiments,the pharmaceutical composition may include any amount or combination ofmicrocrystalline cellulose, mannitol, sodium, crospovidone,croscarmellose magnesium stearate, or any combination thereof.

In some embodiments of the various methods, the pharmaceuticalcompositions including a compound of formula A-1 through A-44 or B-1through B-7, or a pharmaceutically acceptable salt thereof, may beprepared as suspensions, solutions, or emulsions in oily or aqueousvehicles suitable for injection. In such embodiments, such liquidformulations may further include formulatory agents such as suspending,stabilizing, and/or dispersing agents formulated for parenteraladministration. Such injectable formulations may be administered by anyroute, including but not limited to, for example, subcutaneous,intravenous, intramuscular, intra-arterial, bolus injection, orcontinuous infusion, and in embodiments in which injectable formulationsare administered by continuous infusion, such infusion may be carriedout for a period of about fifteen minutes to about twenty-four hours. Incertain embodiments, formulations for injection can be presented in unitdosage form, such as, for example, in ampoules or in multi-dosecontainers, with an added preservative.

In other embodiments of the various methods, a compound of formula A-1through A-44 or B-1 through B-7, or a pharmaceutically acceptable saltthereof, may be formulated as a depot preparation, and such long actingformulations can be administered by implantation, such as, for example,subcutaneously or intramuscularly, or by intramuscular injection. Depotinjections can be administered at about one to about six months orlonger intervals. Thus, for example, the compounds can be formulatedwith suitable polymeric or hydrophobic materials, for example, as anemulsion in an acceptable oil, or with ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

In still other embodiments, pharmaceutical compositions including acompound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof, may be formulated for buccalor sublingual administration. In such embodiments, the pharmaceuticalcompositions may be prepared as chewable tablets, flash melts, orlozenges formulated in any conventional manner known in the art.

In yet other embodiments, pharmaceutical compositions including acompound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof, may be formulated foradministration by inhalation. In such embodiments, pharmaceuticalcompositions according to the various methods may be delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer with the use of a suitable propellant, such as, for example,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol pack, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

In further embodiments, pharmaceutical compositions including a compoundof formula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, can be formulated in rectal compositions suchas suppositories or retention enemas, for example, containingconventional suppository bases such as cocoa butter or other glycerides.

In some embodiments, pharmaceutical compositions including a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, may be formulated for transdermaladministration. Such pharmaceutical compositions may be prepared, forexample, to be applied to a plaster or applied by transdermal,therapeutic systems that are supplied to the subject. In otherembodiments, pharmaceutical and therapeutic compositions including acompound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof, for transdermal administrationmay include suitable solid or gel phase carriers or excipients such as,but not limited to, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such as,for example, polyethylene glycols.

In some embodiments, pharmaceutical compositions including a compound offormula A-1 through A-44 or B-1 through B-7, or a pharmaceuticallyacceptable salt thereof, may be administered alone as a singletherapeutic agent. In other embodiments, pharmaceutical compositionsincluding a compound of formula A-1 through A-44 or B-1 through B-7, ora pharmaceutically acceptable salt thereof, may be administered incombination with one or more other active ingredients, such as, forexample, adjuvants, protease inhibitors, or other compatible drugs orcompounds where such combination is seen to be desirable or advantageousin achieving the desired effects of the methods described herein.

In embodiments, the method further comprises administering one or moreactive agent simultaneously or concurrently with administering acompound of formula A-1 through A-44 or B-1 through B-7, or apharmaceutically acceptable salt thereof. In embodiments, the one ormore active agent is dexpramipexole, riluzole, baclofen, tizanidine, oredaravone. Riluzole is a neuroprotective agent that blocks sodiumchannels in their inactivated states. Riluzole has been shown to prolongsurvival in t subjects with ALS. In embodiments, riluzole isadministered at 50 mg once or twice daily. In embodiments,dexpramipexole is administered at 150 mg a total daily dose of or 300 mgor 600 mg. In embodiments, baclofen is administered at 0.05 mg, 0.5 mg,1 mg, 2 mg, 5 mg, 10 mg, or 20 mg. In embodiments, tizanidine isadministered at 2 mg, 4 mg, or 6 mg. In embodiments, edaravone isadministered at 30 mg. In embodiments, the one or more active agent isdexpramipexole. In embodiments, the one or more active agent isriluzole.

In embodiments, the one or more active agent is an anti-glutamatergic orion channel blocker such as, but are not limited to, FP-0011, memantine,N-acetylated-a-linked acidic dipeptidase (NAALADase) inhibitors,nimodipine, or combination thereof. Excessive glutamate levels have beenshown to be toxic to neurons, and evidence suggests that both direct andindirect glutamate toxicity may contribute to the pathogenesis of motorneuron degeneration in diseases such as ALS. FP0011 is anantiglutamatergic compound that may reduce presynaptic glutamate levelsand shows strong neuroprotective properties. Memantine is anoncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that hasbeen shown to protect neurons against NMDA or glutamate-induced toxicityin vitro and in animal models of neurodegenerative diseases. Inembodiments, memantine is administered at 2 mg, 5 mg, 7 mg, 10 mg, 14mg, 21 mg, or 28 mg. N-Acetylated-Alpha-Linked-Acidic-Dipeptidase(NAALADase) converts N-Acetyl-Aspartyl-Glutamate into glutamate duringneuronal damage and may represent a new approach to block the release ofexcess glutamate without interfering with normal brain function intreatment of neurodegenerative disorders. Nimodipine is adihydropyridine calcium channel blocker which may antagonize excitatoryamino acid receptor activation decreasing calcium entry into damagedneurons and might help to slow or reverse ALS. In embodiments,nimodipine is administered at 30 mg or 60 mg.

In embodiments, the one or more active agent is a mitochondrial energypromoter such as, but are not limited to, resveratrol, creatine,erythropoietin, cholest-4-en-3-One, oxime (TRO-19622) and combinationsthereof. Resveratrol is a powerful antioxidant found in red grape skinsthat has been found to suppress the influx of calcium into cellsassociated with glutamate-induced cell toxicity. In embodiments,resveratrol is administered at 100 mg, 500 mg, 1000 mg, or 1500 mg.Creatine aids in the formation of ATP, the primary source of cellularenergy in the body, and has been shown to provide protective mechanismsagainst neurodegenerative disorders by stabilizing cellular membranesand mitochondrial energy-transfer complexes which may reduce motorneuron death by improving mitochondrial function. Creatine may alsoreduce oxidative stress and increase glutamate uptake and may helpreduce the loss of muscle strength in ALS patients. In embodiments,creatine is administered at about 750 mg to about 5 grams.Erythropoietin (EPO) is a glycoprotein hormone that controlserythropoiesis, red blood cell production that has recently beenidentified as a cytokine with various neuroprotective effects,including, for example, reduction of inflammation, enhancement ofsurvival signals, and prevention of neuronal cell death.Cholest-4-en-3-one, oxime (TRO-19622) is a low molecular-weight compoundshown to enhance motor neuron survival and growth by interacting withprotein components of the mitochondrial permeability transition pore andthat may rescue motor neuron cell bodies from axonomy-induced cell deathin vivo. In embodiments, the one or more active agent is creatine.

1-33. (canceled)
 34. A method of treating a Kv7 associated disorderselected from the group consisting of epilepsy, pain, neuropathic pain,inflammatory pain, persistent pain, cancer pain, postoperative pain,tinnitus, epileptic encephalopathy, treatment-resistant epilepsy,congenital neurological disorder with intellectual disability orepileptic encephalopathy, severe epileptic encephalopathies, congenitalneurodevelopmental disorder with phenotypes of nonsyndromic intellectualdisability or epileptic encephalopathy, epileptic spasms, epilepticencephalopathy, early infantile epileptic encephalopathy 7, earlyinfantile epileptic encephalopathy with delayed psychomotor development,and combinations thereof, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound represented by a formula:

wherein D is optionally substituted cyclobutyl, optionally substitutedphenyl, or optionally substituted C₂₋₅ alkyl, wherein the optionalsubstituents are selected from —CH₃ and F; A is C₁ alkyl; X issubstituted cyclobutyl, wherein the substituent is F; Y is H; R¹ isselected from H, C₃ hydroxyalkyl, CN, F, or Cl; R² is selected from H,CN, F, Br, or —OCF₃; R³ is selected from H, F, or —OCH₃; R⁴ is H or F;wherein when X is substituted with 2 fluorine atoms, the fluorine atomsare not geminal; or a pharmaceutically acceptable salt thereof; andwherein the subject is treated.
 35. The method of claim 34, wherein thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 36. The method of claim34, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 37. The method of claim34, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 38. The method of claim35, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 39. The method of claim35, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 40. The method of claim35, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 41. The method of claim36, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 42. The method of claim36, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 43. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 44. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 45. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 46. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 47. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 48. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 49. The method of claim37, wherein the compound is

or a pharmaceutically acceptable salt thereof.